JKU

**The ALPL Gene Variant Database**

OMIM *171760

Welcome to the ALPL gene mutations database. This site has been compiled to provide up-to-date information about genetic variation of the ALPL gene responsible for hypophosphatasia.

Hypophosphatasia (MIM 146300, 241500, 241510)

The ALPL gene (also called TNSALP; ID:249; MIM 171760), is localized on chromosome 1p36.12 and encodes tissue nonspecific alkaline phosphatase (TNSALP). Pathogenic loss of function mutations in ALPL cause hypophosphatasia (HPP), a rare, multisystemic condition that decreases mineralisation of bones and teeth and causes early loss of baby teeth, muscle weakness and joint pain. In its most severe, recessively inherited perinatal and infantile forms, which untreated have a very high mortality, HPP is also associated with pulmonary hypoplasia with respiratory failure, vitamin B6 responsive seizures, failure to thrive, craniosynostosis and severe rickets-like features. HPP can present or manifest at any age since the phenotypic spectrum is a continuum. Traditional classification into prenatal benign (ORPHA247638), perinatal lethal (ORPHA 247623), infantile (ORPHA 247651), childhood (ORPHA 247667), adult (ORPHA 247676) and odonto HPP (ORPHA 247685) is under debate. The prevalence of severe forms is low (estimated at 1/300,000 in Europe, 1/100,000 in North America), whereas less severe forms are more frequently observed (estimated at 1/6000 in Europe).

Low serum alkaline phosphatase (ALP) is a hallmark diagnostic feature of HPP. However, the condition requires genetic confirmation since ALP can be low for various reasons.(Saraff et al, 2016, Riancho-Zarrabeitia et al, 2016)

The global HPP registry is collecting real-world data to capture the phenotypic spectrum, natural course of disease and the response to enzyme replacement therapy with asfotase alfa. Other approaches, such as gene therapy, are currently being investigated (Ikeue et al. 2018, Nakamura-Takahashi A et al 2020). For more information on HPP, also consult Orphanet.

ALPL gene variants

More than 400 ALPL variants have been identified which are responsible for the extraordinary clinical heterogeneity. A clear but imperfect genotype-phenotype correlation has been observed, suggesting that other genetic or environmental factors modulate the phenotype.

According to ACGM criteria, variants can be classified into benign (1), likely benign (2), unknown significance (3), likely pathogenic (4) and pathogenic (5). This database aims to assist physicians, geneticists, researchers and anyone with interest in HPP to retrieve the most detailed and up-to-date of information on every ALPL variant described to date.

Until January 2021, this site was hosted by the University of Versailles (Prof Etienne Mornet). Our new site at the Johannes Kepler University Linz, Austria (JKU) builds on this work and strives to provide continuously updated, detailed variant-specific data on ALPL genotypes and associated phenotypes, variant classification according to ACGM criteria and in-vitro enzyme activity compared to wild type, as well as information on dominant negative effects.

The HPP gene variant consortium

Prof Wolfgang Högler leads a consortium of researchers, endocrinologists, osteologists, basic scientists and geneticists. The consortium meets regularly to assess research results from in-vitro testing in order to re-classify variants. The Members are: Priya Kishnani; Catherine Rehder; Cheryl Rockman-Greenberg; Kathryn Dahir; Gabriel Martos-Moreno; Agnes Linglart; Keiichi Ozono; Eric Rush; Severine Bacrot; Lothar Seefried; Guillermo del Angel; Gerald Webersinke; Ahmed El-Gazzar; Wolfgang Högler (Consortium Lead, JKU Linz, Austria).

Submission of new variants and functional testing of VUS

Our research lab at JKU Linz, Austria has the capacity and the funding (externally sponsored research agreement, Alexion Pharmaceuticals, Inc) to conduct functional testing of VUS submitted to us. Clinicians and geneticists are encouraged to report any new ALPL variant to this site and thereby assist us in keeping it complete and up-to-date.

For submission of variants, please contact Email: HPPresearch@jku.at

Table of mutations

Nucleotide numbering: -200_-105 / -104_60 / 61_180 / 181_296 / 297_ 471 / 472_647 / 648_791 / 792_861 / 862_996 / 997_1088 / 1089_1308 / 1309_2336

Exon	Base change	Amino acid change (standardized nomenclature)	Pathogenicity	Amino acid change (Non standardized nomenclature)	Reference	Clinical form of the patient	Genotype of the patient	Residual activity		Dominant negative effect		Conservation
Exon	Base change	Amino acid change (standardized nomenclature)	Pathogenicity	Amino acid change (Non standardized nomenclature)	Reference	Clinical form of the patient	Genotype of the patient	% WT	reference	% 50/50	reference	Conservation
1	c.-195C>T		P		Taillandier et al. 2000	perinatal	c.[-195C>T];[602G>A]					na
2	c.3G>A	p.Met1Ile	LP	Met-17Ile	Mentrup et al. 2011	adult	c.[3G>A];[?]	1.0	Mentrup et al. 2011	59.0	Mentrup et al. 2011	++
2	c.17T>A	p.Leu6*	P	Leu-12Ter	Taillandier et al. 2000	childhood	c.[17T>A];[?]					na
2	c.18del	p.Val7Tyrfs	P	Val-11Tyrfs	Cui et al. 2012	infantile	c.[18del];[407G>C]					na
2	c.29T>C	p.Ile10Thr	P	Ile-8Thr	Versailles lab June 2017	infantile	c.[29T>C];[29T>C]	29.2	del Angel et al. 2020	64.9	del Angel et al. 2020	+
2	c.41T>C	p.Leu14Pro		Leu-4Pro	Versailles lab Jul 2010	adult	c.[41T>C];[571G>A]					+
2	c.46_49del	p.Asn16Profs		pAsn-2Profs	Versailles lab March 2011 de Roo et al. 2014	infantile infantile	c.[46_49del];[668G>A]					na
2	c.50C> T	p.Ser17Phe	P	Ser-1Phe	Mornet et al. 1998	infantile	c.[50C> T];[223G>A]	19.0	Zurutuza et al. 1999			+
2	c.61G>A	p.Glu21Lys	P	Glu4Lys	Research center for medical genetics, Moscow, Apr. 2015	adult	c.[.61G>A];[?]					++
IVS2	c.62-1G>A				Versailles lab Feb. 2019	adult	c.[62-1G>A];[=]					na
IVS2	c.62-1G>C		P		Versailles lab March 2013	perinatal		na
3	c.69_74del	p.Glu4_Lys5del			Versailles lab May 2012	perinatal	c.[69_74del];[146A>T]					na
3	c.82T>G	p.Tyr28Asp	P	Tyr11Asp	Yang et al. 2013	odonto	c.[82T>G];[1162T>C]	0	Yang et al. 2013	45	Yang et al. 2013	++
3	c.83A>G	p.Tyr28Cys	P	Tyr11Cys	Taillandier et al. 2001	infantile	c.[83A>G];[407G>A]	7.2	Taillandier et al. 2001			++
3	c.85T>C	p.Trp29Arg	P	Trp12Arg	Chen et al. 2017	childhood	c.[85T>C];[1559del]	4.1	Chen et al. 2017	33.7	Chen et al. 2017	++
3	c.88C>T	p.Arg30*	P	Arg13Ter	Versailles lab Dec 2010	perinatal	c.[88C>T];[385G>A]					na
3	c.94C>T	p.Gln32*		Gln15Ter	Versailles lab. Apr 2011	perinatal	c.[94C>T];[648+1G>A]					na
3	c.97G>C	p.Ala33Pro		Ala16Pro	University of Brasilia Lab, July 2016	infantile	c.[97G>C;112A>G];[1307A>G]					+
3	c.98C>T	p.Ala33Val	P	Ala16Val	Henthorn et al. 1992 Reis et al. 2020	childhood infantile	c.[98C>T];[1306T>C] c.[98C>T];[98C>T]	12.0	del Angel et al. 2020	62.6	del Angel et al. 2020	+
3	c.106A>C	p.Thr36Pro		Thr19Pro	Versailles lab Nov 2008	perinatal	c.[106A>C];[106A>C]					++
3	c.110T>C	p.Leu37Pro	P	Leu20Pro	Versailles lab oct. 2003 del Angel et al. 2020	perinatal	c.[110T>C];[110T>C]					++
3	c.[113_116del ; 118_119insG]	p.Lys38_Tyr39delinsMet		p.Lys21_Tyr22delinsMet	Versailles lab Dec. 2017	adult	c.[113_116del;118_119insG];[=]					na
3	c.119C>T	p.Ala40Val	P	Ala23Val	Mornet et al. 1998 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	perinatal perinatal perinatal infantile infantile	c.[119C>T];[1417C>T] c.[119C>T];[1172G>A] c.[119C>T];[395C>T] c.[119C>T];[746G>T] c.[119C>T;[1142A>G]	2.3 6.9	Zurutuza et al. 1999 del Angel et al. 2020	51.3 87.0	Lia-Baldini et al. 2001 del Angel et al. 2020	+
3	c.129del	p.Gln44Argfs	P	Gln27Argfs	Whyte et al. 2015	childhood	c.[129del];[1307A>G]					na
3	c.130C>T	p.Gln44*	P	Gln27Ter	Mornet et al. 2020	perinatal	c.[130C>T];[662dup]					na
3	c.140A>T	p.Asn47Ile		Asn30Ile	Saglam et al. 2017	perinatal adult	c.[140A>T];[140A>T] c.[140A>T];[=]					++
3	c.146A>T	p.Asn49Ile		Asn32Ile	Versailles lab May 2012	perinatal	c.[69_74del];[146A>T]					+
3	c.151G>T	p.Ala51Ser	P	Ala34Ser	Mumm et al. 2002	infantile	c.[151G>T];[400_401delinsCA]					++
3	c.152C>T	p.Ala51Val	P	Ala34Val	Taillandier et al. 2001 del Angel et al. 2020	infantile perinatal	c.[152C>T];[1375G>A] c.[152C>T];[152C>T]	4.4	del Angel et al. 2020	52.3	del Angel et al. 2020	++
3	c.165_167del	p.Ile55del	LP	Ile38del	del Angel et al. 2020	perinatal	c.[165_167del];[648+1G>A]
3	c.178G>C	p.Asp60His	VUS	Asp43His	McKiernan et al.2017	asymptomatic*	c.[178G>C];[=]
3	c.180T>G	p.Asp60Glu	P	Asp43Glu	Whyte et al. 2015	childhood	c.[180T>G];[=]					++
IVS3	c.182-2A>C		P		Whyte et al. 2015	childhood	c.[182-2A>C];[=]					na
IVS3	c.182-3C>A				Mornet et al. 2020	infantile	c.[182-3C>A];[407G>A]					na
4	c.184A>T	p.Met62Leu	P	Met45Leu	Taillandier et al. 1999	infantile	c.[184A>T];[1172del]	27.4	Zurutuza et al. 1999			++
4	c.184A>G	p.Met62Val	P	Met45Val	Spentchian et al. 2003	infantile	c.[184A>G];[184A>G]					++
4	c.186G>C	p.Met62Ile	P	Met45Ile	Taillandier et al.2005	childhood	c.[186G>C];[571G>A]	0	Taillandier et al.2005			++
4	c.187G>C	p.Gly63Arg	P	Gly46Arg	Spentchian et al. 2003	infantile	c.[187G>C];[187G>C]					++
4	c.187_205del19	p.Gly63Leufs			Versailles lab Jan 2010 Taillandier et al. 2017	adult	c.[187_205del];[=]					na
4	c.188_205dup18	p.Gly63_Thr68dup	P		Guanabens et al. 2013	adult	c.[188_205dup18];[?]					na
4	c.188G>T	p.Gly63Val	P	Gly46Val	Lia-Baldini et al. 2001	infantile	c.[188G>T];[=]	0.8	Lia-Baldini et al. 2001	26.0	Lia-Baldini et al. 2001	++
4	c.194C>A	p.Ser65Tyr		Ser48Tyr	Saglam et al. 2017	perinatal	c.[194C>A];[194C>A]
4	c.203C>T	p.Thr68Met	P	Thr51Met	Orimo et al. 2002 Mao et al.2019 del Angel et al. 2020 del Angel et al. 2020	childhood childhood perinatal adult	c.[203C>T];[529G>A] c.[203C>T];[571G>A] c.[203C>T];[814C>T] c.[203C>T];[=]	5.2 3.0	Orimo et al. 2001 del Angel et al. 2020	36.7	del Angel et al. 2020	++
4	c.202_204del	p.Thr68del		Thr51del	communicated by S. Lazarus, Royal Brisbane &Women's Hospital, Herston, Australia	adult	c.[202_204del];[=]					na
4	c.208G>A	p.Ala70Thr	VUS	Ala53Thr	communicated by Dr S. Brugge r and T. Brown (Alexion)	Mild form. Patient with low AP and unspecific symptoms	c.[208G>A];[208G>A]					+
4	c.211C>T	p.Arg71Cys	P	Arg54Cys	Henthorn et al. 1992 del Angel et al. 2020	infantile odonto	c.[211C>T];[811A>C] c.[211C>T];[=]	0 7.7	Fukushi-Irié et al. 2000 del Angel et al. 2020	35.0 33.2	Fauvert et al. 2009 del Angel et al. 2020	++
4	c.211C>G	p.Arg71Gly	P	Arg54Gly	Research center for medical genetics, Moscow, June 2015 Tenorio et al. 2017	adult childhood	c.[211C>G];[=] c.[211C>G];[=]					++
4	c.211C>A	p.Arg71Ser	P	Arg54Ser	Orimo et al. 2002	childhood	c.[211C>A];[?]	2.9	Orimo et al. 2001			++
4	c.212G>C	p.Arg71Pro	P	Arg54Pro	Henthorn et al. 1992	perinatal	c.[212G>C];[620A>C]	4.1	del Angel et al. 2020	59.8	del Angel et al. 2020	++
4	c.212G>A	p.Arg71His	P	Arg54His	Taillandier et al. 200 1 Mao et al.2019 Reibel et al. 2009	perinatal childhood odonto	c.[119C>T];[212G>A] c.[212G>A];[571G>A] c.[212G>A];[=]	1.0 6.6	Fauvert et al. 2009 del Angel et al. 2020	30.5 32.5	Fauvert et al. 2009	++
4	c.215T>C	p.Ile72Thr	P	Ile55Thr	Versailles lab oct. 2004	odonto	c.[215T>C];[=]	5.1	Fauvert et al. 2009	40.2	Fauvert et al. 2009	++
4	c.214A>G	p.Ile72Val		Ile55Val	Versailles lab dec. 2014	infantile	c.[214A>G];[214A>G]					++
4	c.217_219del	p.Leu73del		Leu56del	Versailles lab aug. 2013 Tenorio et al. 2017	asymptomatic* childhood	c.[217_219del];[=] c.[217_219del];[=]					na
4	c.223G>A	p.Gly75Ser	P	Gly58Ser	Mornet et al. 1998	infantile	c.[50C> T];[223G>A]	3.5	Zurutuza et al. 1999			++
4	c.227A>G	p.Gln76Arg	P	Gln59Arg	Mornet et al. 2001 del Angel et al. 2020	infantile infantile	c.[227A>G];[401C>A] c.[227A>G];[571G>A]	3.0	del Angel et al. 2020	39.8	del Angel et al. 2020	++
4	c.228G>T	p.Gln76His	P
4	c.228del		P		Li et al. 2017	infantile	c.[228del];[407G>A]					na
4	c.242del	p.Pro81Leufs		Pro64Leufs	Versailles lab Jul 2009 del Angel et al. 2020	perinatal	c.[242del];[242del]					na
4	c.247G>T	p.Glu83*		Glu66Ter	Versailles lab Apr 2011	infantile	c.[247G>T];[247G>T]					na
4	c.251A>T	p.Glu84Val	P	Glu67Val	Wei et al. 2010	odonto	c.[251A>T];[?]					+
4	c.252G>C	p.Glu84Asp		Glu67Asp	Whyte et al. 2016	infantile	c.[252G>C];[1375G>A]					+
4	c.262G>A	p.Glu88Lys	P	Glu71Lys	Mohn et al. 2011	infantile	c.[262G>A];[920C>T]					++
4	c.277C>T	p.Pro93Ser	P	Pro76Ser	Peach et al. 2007	prenat. benign	c.[277C>T];[400_401delinsCA]	70.0	del Angel et al. 2020	121	del Angel et al. 2020	++
4	c.283G>A	p.Val95Met	P	Val78Met	Versailles lab Sept 2019	adult	c.[283G>A];[=]	56.8	del Angel et al. 2020	79.6	del Angel et al. 2020	++
4	c.297G>C	p.Lys99Asn		Lys82Asn	Seefried et al. 2017	adult	c.[297G>C];[=]					++
IVS4	c.297+2T>A				Clinvar (Counsyl)	infantile	not provided					na
IVS4	c.297+3G>T		LP		Versailles lab. Jan 2011	infantile	c.[297+3G>T];[299C>T]					na
IVS4	c.298-2A>G		P		Taillandier et al. 2000 Versailles lab Versailles lab	perinatal perinatal odonto	c.[298-2A>G];[997+3A>C] c.[298-2A>G];[407G>A] c.[298-2A>G];[=]					na
IVS4	c.298-1G>A		P		Zhang et al. 2012	adult	c.[298-1G>A];[298-1G>A]					na

5	c.299C>T	p.Thr100Met	P	Thr83Met	Mornet et al. 2001 del Angel et al. 2020 Michigami et al.2020 Taillandier et al. 2015 Maman et al. 2016 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	infantile adult perinatal benign perinatal adult perinatal perinatal childhood	c.[299C>T];[571G>A] c.[299C>T];[571G>A] c.[299C>T];[982T>C] c.[299C>T];[1258G>A] c.[299C>T];[571G>A] c.[299C>T];[227A>G] c.[299C>T];[299C>T] c.[299C>T];[=]	1.3 5.8	Fauvert et al. 2009 del Angel et al. 2020	28.2 32.4	Fauvert et al. 2009 del Angel et al. 2020	++
5	c.301T>G	p.Tyr101Asp		Tyr84Asp	Versailles lab. Feb 2012	odonto	c.[301T>G];[=]					++
5	c.303C>A	p.Tyr101*	P	Tyr84Ter	Alonso et al. 2019	adult with unspecific signs (osteoporosis)	c.[303C>A];[=]					na
5	c.303_311del	p.Asn102_Asn104del	P	Asn85_Asn87del	del Angel et al. 2020 del Angel et al. 2020	perinatal adult	c.[303_311del];[1471G>A] c.[303_311del];[=]	2.6	del Angel et al. 2020	26.3	del Angel et al. 2020	na
5	c.311A>G	p.Asn104Ser	P	Asn87Ser	Bhadada et al. 2020	Adult	c.[311A>G];[=]					++
5	c.314C>A	p.Ala105Asp		Ala88Asp	Communicated by Sue Krug Soft Bones U.S. Oct. 2018	adult	c.[314C>A];[=]	2.7	del Angel et al. 2020	40.4	del Angel et al. 2020	++
5	c.317A>G	p.Gln106Arg		Gln89Arg	Communicated by Dr M.G. Benzrihen, Hospital Alejandro Posedas, Argentina	childhood	c.[317A>G];[=]					++
5	c.318G>C	p.Gln106His	LP	Gln89His	Balasubramaniam et al. 2010	perinatal	c.[318G>C];[318G>C]					++
5	c.323C>T	p.Pro108Leu	P	Pro91Leu	Herasse et al. 2003	odonto	c.[323C>T];[=]	1.9	Fauvert et al. 2009	24.0	Fauvert et al. 2009	++
5	c.327C>A	p.Asp109Glu		Asp92Glu	Bone Metabolism Unit, Instituto Auxologico Italiano IRCCS, Milano, Italy	adult	c.[327C>A];[327C>A]					++
5	c.331G>A	p.Ala111Thr	P	Ala94Thr	Goseki-Sone et al. 1998 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 Zankl et al. 2008	odonto odonto perinatal perinatal perinatal	c.[331G>A];[=] c.[331G>A];[=] c.[331G>A];[331G>A] c.[331G>A];[1354G>A] c.[331G>A];[c.400_401delinsCA]	2.0 3.4	Fauvert et al. 2009 del Angel et al. 2020	48.7 51.1	Fauvert et al. 2009 del Angel et al. 2020	++
5	c.332_335del	p.Gly111fs			Mornet et al. 2020	infantile	c.[332_335del];[1471G>A]					na
5	c.333del	p.Gly112Alafs	P	Gly95Alafs	Bai et al. 2016	perinatal	c.[333del];[568_570del]					na
5	c.334G>A	p.Gly112Ser	LP	Gly95Ser	Witters et al. 2004 del Angel et al. 2020 Tenorio et al. 2017 del Angel et al. 2020	infantile infantile adult odonto	c.[334G>A];[1171C>T] c.[334G>A];[571G>A] c.[334G>A];[=] c.[334G>A];[=]					++
5	c.334G>C	p.Gly112Arg	P	Gly95Arg	Whyte et al. 2015	odonto.	c.[334G>C];[=]					++
5	c.335_340dup	p.Gly112_113dup	P	Gly95_96dup	Wenkert et al. 2011	prenatal benign	c.[335_340dup];[571G>A]					na
5	c.340G>A	p.Ala114Thr	P	Ala97Thr	Mumm et al. 2001 Whyte et al. 2015 Tenorio et al. 2017 del Angel et al. 2020 del Angel et al. 2020	infantile childhood childhood adult adult	c.[340G>A];[811A>C] c.[340G>A];[=] c.[340G>A];[=] c.[340G>A];[c.407G>A] c.[340G>A];[=]	3.0	del Angel et al. 2020	49.2	del Angel et al. 2020	++
5	c.341C>G	p.Ala114Gly	P	Ala97Gly	Draguet et al. 2004	perinatal	c.[341C>G;348_349insACCGTC];[976G>C]					++
5	c.341C>T	p.Ala114Val	P	Ala97Val	Versailles lab march 2016	adult	c.[341C>T];[=]	5.2	del Angel et al. 2020	45.0	del Angel et al. 2020	++
5	c.344C>T	p.Thr115Ile	P	Thr98Ile	Versailles lab Feb. 2019	odonto	c.[344C>T];[407G>A]	11.4	del Angel et al. 2020	54.3	del Angel et al. 2020	++
5	c.346G>T	p.Ala116Ser	P	Ala99Ser	Versailles lab Jul 2007	adult	c.[346G>T];[1250A>G]					++
5	c.346G>A	p.Ala116Thr	P	Ala99Thr	Hu et al. 2000 Lia-Baldini et al. 2001 Saglam et al. 2017 Saglam et al. 2017 Taillandier et al. 2015 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	adult adult odonto childhood childhood adult infantile perinatal	c.[346G>A];[=] c.[346G>A];[=] c.[346G>A];[=] c.[346G>A];[=] c.[346G>A];[=] c.[346G>A];[571G>A] c.[346G>A];[571G>A] c.[346G>A];[631A>G]	0.8 3.7	Lia-Baldini et al. 2001 del Angel et al. 2020	40.0 27.0	Lia-Baldini et al. 2001 del Angel et al. 2020	++
5	c.343_348dup	p.Thr115_Ala116dup	P	Thr98_Ala99dup	Draguet et al. 2004 Versailles lab March 2009 Tenorio et al. 2017	perinatal odonto childhood	c.[Ala116Gly+343_348dup];[976G>C] c.[343_348dup];[=] c.[343_348dup];[=]					na
5	c.350A>G	p.Tyr117Cys	P	Tyr100Cys	Whyte et al. 2009 del Angel et al. 2020	childhood adult	c.[350A>G];[400_401delinsCA] c.[350A>G];[=]					+
5	c.352C>A	p.Leu118Met	P	Leu101Met	Riancho-Zarrabeitia et al. 2016	asymtomatic* or very mild symptoms	c.[352C>A];[352C>A]	50.0	del Angel et al. 2020	108	del Angel et al. 2020	++
5	c.358G>A	p.Gly120Arg	P	Gly103Arg	Mornet et al. 1998	perinatal	c.[358G>A];[648+1G>A]					++
5	c.359G>C	p.Gly120Ala	LP	Gly103Ala	Mao et al.2019	infantile	c.[359G>C];[359G>C]					++
5	c.360_361del	p.Val121Glufs		Val104Glufs	Vidmar et al. 2017	perinatal	c.[360_361del];[46_49del]					na
5	c.361G>A	p.Val121Met		Val104Met	Versailles lab dec. 2015 Lefever et al. 2018	childhood adult	c.[361G>A];[=] c.[361G>A];[=]					++
5	c.368C>A	p.Ala123Asp	P	Ala106Asp	Spentchian et al. 2006	perinatal	c.[368C>A];[797_802del]					+
5	c.379A>G	p.Thr127Ala		Thr110Ala	Seefried et al. 2017	Adult	c.[379A>G];[526G>A]					++
5	c.382G>A	p.Val128Met	P	Val111Met	Mumm et al. 2002 Tenorio et al. 2017 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	perinatal adult childhood childhood infantile childhood	c.[382G>A];[667C>T] c.[382G>A];[=] c.[382G>A];[382G>A] c.[382G>A];[395C>T] c.[382G>A];[1016G>A] c.[382G>A];[395C>T]	60.6	del Angel et al. 2020	68.5	del Angel et al. 2020	+
5	c.388_389insG	p.Val130Glyfs		Val113Glyfs	Riancho-Zarrabeitia et al. 2016 Tornero et al. 2020	asymtomatic* or very mild symptoms	c.[388_389insG];[?]					na
5	c.385G>A	p.Gly129Arg	P	Gly112Arg	Mornet et al. 1998	perinatal	c.[385G>A];[1471G>A]					++
5	c.389_392del	p.Val130Alafs		Val113Alafs	Spentchian et al. 2003	perinatal	c.[389_392del];[931G>A]					na
5	c.389del	p.Val130Glufs	P	Val113Glufs	Spentchian et al. 2003	perinatal	c.[389del];[389del]					na
5	c.392del	p.Ser131Thrfs	P	Ser114Thrfs	Mumm et al. 2002	perinat/infant	c.[392del];[1042G>A]					na
5	c.394G>A	p.Ala132Thr	P	Ala115Thr	Versailles lab Jul 2006 del Angel et al. 2020	adult odonto	c.[394G>A];[571G>A] c.[394G>A];[407G>A]					++
5	c.395C>T	p.Ala132Val	P	Ala115Val	Watanabe et al. 2001	adult	c.[395C>T];[?]	16.9	Watanabe et al. 2005			++
5	c.400_401delinsCA	p.Thr134His	P	Thr117His	Mumm et al. 2002 Daniel et al. 2018 del Angel et al. 2020 del Angel et al. 2020	perinatal childhood perinatal perinatal	c.[400_401delinsCA];[984_986del] c.[400_401delinsCA];[350A>G] c.[400_401delinsCA];[400_401delinsCA] c.[400_401delinsCA];[382G>A]	13.8	del Angel et al. 2020	81.7	del Angel et al. 2020	+
5	c.401C>A	p.Thr134Asn	P	Thr117Asn	Taillandier et al. 2000	perinatal	c.[401C>A];[401C>A]	20.5 34.5	Taillandier et al. 2000 del Angel et al. 2020	129.2	del Angel et al. 2020	+
5	c.406C>T	p.Arg136Cys	P	Arg119Cys	Versailles lab oct. 2003 Schmidt et al. 2017	odonto adult	c.[406C>T];[407G>A] c.[406C>T];[=]	5.0	del Angel et al. 2020	78.1	del Angel et al. 2020	++
5	c.407G>A	p.Arg136His	P	Arg119His	Taillandier et al. 1999 Whyte et al. 2015 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 Tenorio et al. 2017 del Angel et al. 2020	infantile infantile odonto adult childhood adult adult adult adult	c.[407G>A];[485G>T] c.[407G>A];[212G>A] c.[407G>A];[406C>T] c.[407G>A];[512A>G] c.[407G>A];[889T>G] c.[407G>A];g.[(?_64307)_(64441_?)del] c.[407G>A];[=] c.[407G>A];[=] c.[407G>A];[984_986del]	33.4 21.2	Zurutuza et al. 1999 del Angel et al. 2020	70.0 71.2	Fauvert et al. 2009 del Angel et al. 2020	++
5	c.407G>T	p.Arg136Leu	P	Arg119Leu	Yang et al. 2013	childhood	c.[407G>T];[1166C>A]	35	Yang et al. 2013	62	Yang et al. 2013	++
5	c.407G>C	p.Arg136Pro	P	Arg119Pro	Cui et al. 2012	infantile	c.[18del];[407G>C]					++
5	c.412_413dupC	p.Arg138Profs		Arg121Profs	Xu et al. 2018	childhood	c.[412_413dupC];[=]					na
5	c.413G>C	p.Arg138Pro		Arg121Pro	Castells et al. 2018	perinatal	c.[413G>C];[473-2G>C]?	3.2	del Angel et al. 2020	44.2	del Angel et al. 2020	+
5	c.416G>A	p.Cys139Tyr		Cys122Tyr	Collagen Diagnosis Laboratory, University of Washington, USA, Febr. 2018	childhood	c.[416G>A];[=]	9.5	del Angel et al. 2020	64.8	del Angel et al. 2020	++
5	c.422C>A	p.Thr141Asn	P	Thr124Asn	Whyte et al. 2015	childhood	c.[422C>A];[629A>G]					++
5	c.422C>T	p.Thr141Ile	P	Thr124Ile	Versailles lab Jul 2008 del Angel et al. 2020	infantile infantile	c.[422C>T];[920C>T] c.[422C>T];[422C>T]	61.5	del Angel et al. 2020	120	del Angel et al. 2020	++
5	c.427del	p.Gln143Argfs	P	Gln126Argfs	Whyte et al. 2015	childhood	c.[427del];[1444C>A]					na
5	c.431G>A	p.Gly144Glu	P	Gly127Glu	Versailles lab April 2018	adult	c.[431G>A];[=]	82.3	del Angel et al. 2020	94.9	del Angel et al. 2020	++
5	c.436G>A	p.Glu146Lys	VUS	Glu129Lys	Nielson et al. 2012 Alonso et al. 2019	asymptomatic*, low BMD adult with unspecific signs (osteoporosis)	c.[436G>A];[=]	72.7	del Angel et al. 2020	96.1	del Angel et al. 2020	++
5	c.442A>G	p.Thr148Ala	P	Thr131Ala	Michigami et al. 2005	perinatal	c.[442A>G];[?]					++
5	c.443C>T	p.Thr148Ile	P	Thr131Ile	Spentchian et al. 2003 del Angel et al. 2020 Tenorio et al. 2017	infantile childhood adult	c.[443C>T];[484G>A] c.[443C>T];[443C>T] c.[443C>T];[=]	24.9	del Angel et al. 2020	91.6	del Angel et al. 2020	++
5	c.454C>T	p.Arg152Cys	P	Arg135Cys	Versailles lab Nov. 2009 Martins et al. 2013	adult odonto	c.[454C>T];[550C>T] c.[454C>T];[1318_1320del]	49.9	del Angel et al. 2020	75.1	del Angel et al. 2020	+
5	c.457T>C	p.Trp153Arg	P	Trp136Arg	Wenkert et al. 2011	prenatal benign	c.[1183A>G];[457T>C]					++
5	c.461C>T	p.Ala154Val		Ala137Val	Yu et al. 2019	perinatal	c.[461C>T];[406C>T]					++
5	c.466G>T	p.Asp156Tyr		Asp139Tyr	Taillandier et al. 2017	Adult	c.[466G>T];=]					+
IVS5	c.472+1G>A		P		Liu et al. 2010	odonto	c.[472+1G>A];[1120G>A]					na
IVS5	c.473-2A>G		P		Riancho-Zarrabeitia et al. 2016	asymtomatic* or very mild symptoms	c.[473-2A>G];[?]					na

6	c.480del		P		Versailles lab. Jan. 2008	perinatal	c.[480del];[667C>T]					na
6	c.484G>A	p.Gly162Ser	P	Gly145Ser	Spentchian et al. 2003 del Angel et al. 2020 del Angel et al. 2020	infantile perinatal adult	c.[484G>A];[443C>T] c.[484G>A];[407G>A] c.[484G>A];[=]	19.3	del Angel et al. 2020	75.1	del Angel et al. 2020	++
6	c.485G>T	p.Gly162Val	P	Gly145Val	Taillandier et al. 1999	infantile	c.[407G>A];[485G>T]	1.3	Zurutuza et al. 1999			++
6	c.491T>G	p.Val164Gly		Val147Gly	Versailles lab March 2009	infantile	c.[491T>G];[811A>C]					++
6	c.494C>T	p.Thr165Ile	P	Thr148Ile	Versailles lab April 2018	adult	c.[494C>T];[=]	5.6	del Angel et al. 2020	65.6	del Angel et al. 2020	++
6	c.497C>T	p.Thr166Ile	P	Thr149Ile	Riancho-Zarrabeitia et al. 2016	asymtomatic* or very mild symptoms	c.[497C>T];[=]					++
6	c.500C>T	p.Thr167Met	P	Thr150Met	Versailles lab Oct. 2003 Braunstein et al. 2015 Whyte et al. 2015	infantile adult childhood severe	c.[500C>T];[571G>A] c.[500C>T];[=] c.[500C>T];[407G>A]	3.5	del Angel et al. 2020	45.0	del Angel et al. 2020	+
6	c.508A>G	p.Asn170Asp	P	Asn153Asp	Mornet et al. 1998	perinatal	c.[508A>G];[508A>G]	0	Ito et al. 2002			+
6	c.511C>T	p.His171Tyr	P	His154Tyr	Taillandier et al. 1999	infantile	c.[511C>T];[571G>A]	2.1	Zurutuza et al. 1999			++
6	c.512A>G	p.His171Arg	P	His154Arg	Bükmann Larsen et al. 2018 Tenorio et al. 2017 del Angel et al. 2020	adult adult infantile	c.[512A>G];[571G>A] c.[512A>G];[=] c.[512A>G];[542C>T]	4.3	del Angel et al. 2020	37.1	del Angel et al. 2020	++
6	c.518C>T	p.Thr173Ile	P	Thr156Ile	C.V. Lago, Military Police Hospital M.G., Belo Horizonte, Brazil, July 2017	childhood	c.[518C>T];[=]	5.7	del Angel et al. 2020	23.8	del Angel et al. 2020	++
6	c.522del	p.Ser175Alafs		Ser158Alafs	Clinvar (Counsyl)	infantile	not provided					na
6	c.526G>A	p.Ala176Thr	P	Ala159Thr	Taillandier et al. 2000 Stevenson et al. 2008 Reib Reibel et al 2009 Lawrence et al. 2017 Mori et al. 2016 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	childhood prenatal benign odonto childhood adult adult childhood infantile childhood adult odonto	c.[526G>A];[738G>T] c.[526G>A];[814C>T] c.[526G>A];[571G>A] c.[526G>A];[648+1G>A] c.[526G>A];[1171C>T] c.[526G>A];[648+1G>A] c.[526G>A];[881A>C] c.[526G>A];[891C>A] c.[526G>A];[997+2T] c.[526G>A];[=] c.[526G>A];[=]	45.4 67.6	Taillandier et al. 2000 del Angel et al. 2020	58.0 78.4	Fauvert et al. 2009 del Angel et al. 2020	++
6	c.529G>A	p.Ala177Thr	P	Ala160Thr	Goseki-Sone et al. 1998	adult	c.[529G>A];[979T>C]	83.8 81.7	Orimo et al. 2001 del Angel et al. 2020	99.1	del Angel et al. 2020	+
6	c.532T>C	p.Tyr178His	P	Tyr161His	Ikenoue et al. 2017	perinatal	c.[532T>C];[1559del]	0	Ikenoue et al. 2017			++
6	c.535G>A	p.Ala179Thr	P	Ala162Thr	Weiss et al. 1988	perinatal	c.[535G>A]:[535G>A]	18 9.2	Shibata et al.1998 del Angel et al. 2020	64.0	del Angel et al. 2020	++
6	c.538C>A	p.His180Asn		His163Asn	Versailles lab March 2016 Lefever et al. 2018	adult	c.[538C>A];[=]					++
6	c.539A>G	p.His180Arg		His163Arg	Versailles lab Dec. 2018	adult	c.[539A>G];[=]	11.5	del Angel et al. 2020	92.7	del Angel et al. 2020	++
6	c.542C>T	p.Ser181Leu	P	Ser164Leu	Lia-Baldini et al. 2001 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 f del Angel et al. 2020 del Angel et al. 2020 Tenorio et al. 2017 Riancho-Zarrabeitia et al. 2016 Martos-Moreno et al. 2017	infantile perinatal odonto infantile infantile childhood adult adult infantile	c.[542C>T];del(ex12) c.[542C>T];[1250A>G] c.[542C>T];[1282C>T] c.[542C>T];[542C>T] c.[542C>T];[853_854insdel] c.[542C>T];[920C>T] c.[542C>T];[=] c.[542C>T];[=] c.[542C>T];[644T>C]	1.3 55.3	Lia-Baldini et al. 2001 d el Angel et al. 2020	54.4 89.4	del Angel et al. 2020 Lia-Baldini et al. 2001	++
6	c.544del	p.Ala182Leufs	P	Ala165Leufs	Taillandier et al. 1999	perinatal	c.[544del];[746G>T]					na
6	c.547G>C	p.Asp183His	P	Asp166His	Versailles lab Nov 2008	infantile	c.[547G>C];[811A>C]					+
6	c.550C>T	p.Arg184Trp	P	Arg167Trp	Mornet et al. 1998 Michigami et al.2020 del Angel et al. 2020 del Angel et al. 2020	perinatal odonto odonto adult	c.[550C>T];[809G>A] c.[550C>T];[=] c.[550C>T];[=] c.[550C>T];[454C>T]	0.6 0 3.1	Lia-Baldini et al. 2001 Michigami et al.2020 del Angel et al. 2020	36.7 50 44.1	Lia-Baldini et al. 2001 Michigami et al.2020 del Angel et al. 2020	++
6	c.551G>A	p.Arg184Gln	P	Arg167Gln	Versailles lab. Nov. 2013 del Angel et al. 2020 Mornet et al. 2020	infantile adult	c.[551G>A];[203C>T] c.[551G>A];[=]	3.8	del Angel et al. 2020	44.4	del Angel et al. 2020	++
6	c.558G>A	p.Trp186*		Trp169*	Garcia-Fontana et al. 2019 Mornet et al. 2020	adult adult	c.[558G>A];[=] c.[558G>A];[571G>A]					na
6	c.562T>C	p.Ser188Pro	P	Ser171Pro	Oyachi et al. 2018	perinatal	c.[562T>C];[1559del]	2.1	del Angel et al. 2020	63.6	d del Angel et al. 2020	++
6	c.565G>A	p.Asp189Asn		Asp172Asn	communicated by A. O'Brien, Sick Kids Hospital, Toronto, Canada, April 2018	Adult	c.[565G>A];[=]	7.9	del Angel et al. 2020	48.3	del Angel et al. 2020	++
6	c.565_575delinsAG	p.Asp189_Met192delinsArg		Asp172_Met175delinsArg	Dr I. RAU , Institüt für Humangenetik, Hamburg, Germany, Jan 2019	Adult	c.[565_575delinsAG];[=]					na
6	c.567C>A	p.Asp189Glu	P	Asp172Glu	Spentchian et al. 2003	perinatal	c.[567C>A];[567C>A]					++
6	c.568_570del	p.Asn190del	P	Asn173del	Michigami et al. 2005	perinatal	c.[568_570del];[1559del]					na
6	c.571G>A	p.Glu191Lys	P	Glu174Lys	Henthorn et al. 1992 Hofmann et al.2014 Hofmann et al.2014 Mao et al.2019 Mao et al.2019 Versailles lab Jul 2010 Tenorio et al. 2017 Reibel et al. 2009 Lefever et al.2018 del Angel et al. 2020 del Angel et al. 2020 Mornet et al. 2020 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	infantile childhood infantile childhood childhood adult infantile infantile childhood adult prenatal benign infantile infantile childhood childhood, adult, odonto	c.[571G>A];[1133A>T] c.[571G>A];[1001G>A] c.[571G>A];[1001G>A] c.[571G>A];[203C>T] c.[571G>A];[212G>A] c.[571G>A];[41T>C c.[571G>A];[1133A>G] c.[571G>A];[550C>T] c.[571G>A];[1172G>A] c.[571G>A];[1015G>C] c.[571G>A];[1015G>C] c.[571G>A];[1042G>A] c.[571G>A];[1171C>T] c.[571G>A];[1175G>C] c.[571G>A];[=]	88.0 56.0 21.4	Zurutuza et al. 1999 Fauvert et al. 2009 del Angel et al. 2020	79.5 58.7	Fauvert et al. 2009 del Angel et al. 2020	++
6	c.572A>G	p.Glu191Gly		Glu174Gly	Goseki-Sone et al. 1998 Michigami et al.2020 Michigami et al.2020	odonto odonto perinatal benign	c.[572A>G];[1559del] c.[572A>G];[1559del] c.[572A>G];[1559del]					++
6	c.575T>C	p.Met192Thr	P	Met175Thr	Versailles lab Jul 2007 Alonso et al. 2019 A.Rosen, Emory University, Atlanta GA, USA. Jan 2020	infantile adult with unspecific signs (osteoporosis) childhood (mild form)	c.[575T>C];[931G>A] c.[575T>C];[=] c.[575T>C];[=]	57.6	del Angel et al. 2020	1.0	del Angel et al. 2020	++
6	c.577C>G	p.Pro193Ala	P	Pro176Ala	Mumm et al. 2002	adult	c.[340G>A];[577C>G]					+
6	c.599G>A	p.Gly200Asp	P	Gly183Asp	Taillandier et al. 2015	adult	c.[599G>A];[=]					++
6	c.601T>C	p.Cys201Arg		Cys184Arg	Xu et al. 2018	adult	c.[601T>C];[=]					++
6	c.602G>A	p.Cys201Tyr	P	Cys184Tyr	Taillandier et al. 1999	perinatal	c.[-195C>T];[602G>A]	0	Satou et al. 2012			++
6	c.609C>G	p.Asp203Glu	P	Asp186Glu	Versailles lab oct. 2004	perinatal	c.[609C>G];[609C>G]	3.7	del Angel et al. 2020	59.1	del Angel et al. 2020	++
6	c.614C>T	p.Ala205Val		Ala188Val	Versailles lab aug. 2013	asymptomatic*	c.[614C>T];[?]					+
6	c.620A>C	p.Gln207Pro	P	Gln190Pro	Henthorn et al. 1992	perinatal	c.[212G>C];[620A>C]					++
6	c.622C>T	p.Leu208Phe		Leu191Phe	Versailles lab april 2009	perinatal	c.[622C>T];[622C>T]					++
6	c.625A>T	p.Met209Leu	VUS	Met192Leu	Schmidt et al. 2019	adult	c.[625A>T];[746G>T]					+
6	c.629A>G	p.His210Arg	P	His193Phe	Whyte et al. 2015	childhood	c.[422C>A];[629A>G]	20.2	del Angel et al. 2020	78.8	del Angel et al. 2020	+
6	c.630_637dup	p.Arg213Ilefs		Arg196Ilefs	Versailles lab June 2011	perinatal	c.[630_637dup];[792G>A]					na
6	c.631A>G	p.Asn211Asp	P	Asn194Asp	Taillandier et al. 2001	infantile	c.[346G>A];[631A>G]					++
6	c.634A>T	p.Ile212Phe	P	Ile195Phe	Souka et al. 2002	perinatal	c.[634A>T];[1062G>C]					+
6	c.643A>G	p.Ile215Val		Ile198Val		adult	c.[643A>G];[=]					++
6	c.644T>C	p.Ile215Thr		Ile198Thr	Versailles lab. march 2011	infantile	c.[542C>T];[644T>C]					++
IVS6	c.648+1G>T		P		Brun-Heath et al. 2005	perinatal	c.[648+1G>T];[811A>C]					na
IVS6	c.648+1G>A		P		Mornet et al. 1998	perinatal	c.[358G>A];[648+1G>A]					na
IVS6	c.648+2dup				Versailles lab jan 2013 Mentrup et al.2016	perinatal	c.[648+2dup];[1196C>T]					na
IVS6	c.649-3_649-1delinsAA				Versailles lab Jul 2006	perinatal	c.[649-3_649-1delinsAA];[649-3_649-1delinsAA]					na

7	c.650delinsCTAA	p.217delValinsAlaLys		200delValinsAlaLys	Chang et al. 2011	perinatal	c.[650delinsCTAA];[984_986del]					na
7	c.653T>C	p.Ile218Thr	P	Ile201Thr	Utsch et al., 2009	perinatal	c.[653T>C];[1171C>T]	3.7	Utsch et al., 2009			++
7	c.655A>G	p.Met219Val	P	Met202Val	Yang et al. 2013	odonto	c.[655A>G];[331G>A]	75 42.4	Yang et al. 2013 del Angel et al. 2020	80 86.5	Yang et al. 2013 del Angel et al. 2020	+
7	c.657G>T	p.Met219Ile		Met202Ile	Versailles lab, Jan 2019	adult	c.[657G>T];[=]	30.1	d del Angel et al. 2020	77.0	del Angel et al. 2020	+
7	c.658G>A	p.Gly220Arg	P	Gly203Arg	Versailles lab Dec 2011	perinatal	c.[658G>A];[658G>A]					++
7	c.659G>T	p.Gly220Val		Gly203Val	Taillandier et al. 2001	odonto	c.[571G>A];[659G>T]					++
7	c.659G>C	p.Gly220Ala	P	Gly203Ala	Spentchian et al. 2006 del Angel et al. 2020	perinatal infantile perinatal	c.[659G>C];[659G>C] c.[659G>C];[659G>C] c.[659G>C];[668G>A]	23.1	del Angel et al. 2020	66.7	del Angel et al. 2020	++
7	c.661G>C	p.Gly221Arg	P	Gly204Arg	Versailles lab March 2009 del Angel et al. 2020	perinatal perinatal	c.[661G>C];[?] c.[661G>C];[920C>T]	4.2	del Angel et al. 2020	65.2	del Angel et al. 2020	++
7	c.662dup	p.Gly222Trpfs		Gly205Trpfs	Mornet et al. 2020	perinatal	c.[130C>T];[662dup]					na
7	c.662del	p.Gly221Valfs	P	Gly204Valfs	Spentchian et al. 2003	perinatal	c.[662del];[815G>T]					na
7	c.662G>T	p.Gly221Val	P	Gly204Val	Versailles lab oct. 2004	perinatal	c.[662G>T];[1064T>C]					++
7	c.667C>T	p.Arg223Trp	P	Arg206Trp	Mornet et al. 1998	perinatal	c.[667C>T];[?]	2.8	Lia-Baldini et al. 2001	51.9	Lia-Baldini et al. 2001	++
7	c.668G>A	p.Arg223Gln	P	Arg206Gln	Mumm et al. 2002 Mumm et al. 2002 del Angel et al. 2020	perinatal infantile adult	c.[668G>A];[0] c.[668G>A];[881A>C] c.[668G>A];[=]	2.9 5.0	Zhu et al. 2012 del Angel et al. 2020	37.5	del Angel et al. 2020	++
7	c.670A>G	p.Lys224Glu	P	Lys207Glu	Mochizuki et al. 2000	infantile	c.[670A>G];[1276G>T]	43	Michigami et al. 2005			++
7	c.677T>C	p.Met226Thr	P	Met209Thr	Baumgartner-Sigl et al. 2007 Mornet et al. 2020	infantile adult	c.[677T>C];[1112C>T] c.[677T>C];[=]					++
7	c.704A>T	p.Glu235Val		Glu218Val	Michigami et al.2020	odonto	c.[704A>T];[1559del]
7	c.704A>G	p.Glu235Gly	P	Glu218Gly	Taillandier et al. 2001	adult	c.[704A>G];[1195G>T]	3.6 3.3	Mornet et al. 2001 del Angel et al. 2020	62.4	del Angel et al. 2020	++
7	c.708T>G	p.Tyr236*	p	Tyr219*	Vogt et al. 2020	childhood	c.[708T>G];[350A>G]					na
7	c.715G>T	p.Asp239Tyr		Asp222Tyr	Saraff et al. 2016	asymptomatic*	c.[715G>T];[715G>T]					+
7	c.734C>T	p.Thr245Met		Thr228Met	Versailles lab May 2016	prenatal benign? (not confirmed)	c.[734C>T];[?]	59.3	del Angel et al. 2020	88.7	del Angel et al. 2020	++
7	c.738G>T	p.Arg246Ser		Arg229Ser	Taillandier et al. 2000	childhood	c.[526G>A];[738G>T]	4.4 4.5	Taillandier et al. 2000 del Angel et al. 2020	52.0	del Angel et al. 2020	++
7	c.746G>T	p.Gly249Val	P	Gly232Val	Fedde et al. 1996	perinatal	c.[746G>T];[=]	34.5 36.3	Lia-Baldini et al. 2001 del Angel et al. 2020	70.5 80.6	Lia-Baldini et al. 2001 del Angel et al. 2020	+
7	c.791A>G	p.Lys264Arg	P	Lys247Arg	Brun-Heath et al. 2007	perinatal	c.[791A>G];[1133A>T]					+
7	c.792G>A	p.Lys264Lys		Lys247Lys	Versailles lab june 2011	perinatal	c.[792G>A];[630_637dup]					na (splice)
IVS7	c.793-14_33del				Mentrup et al. 2016	infantile	c.[793-14_33del];[793-14_33del]	0	Mentrup et al. 2016	50	Mentrup et al. 2016	na

8	c.797_802del	p.Ser266_His267del	P	Ser249_His250del	Spentchian et al. 2006	perinatal	c.[368C>A];[797_802del]					na
8	c.799_804del	p.His267_Phe268del	P	p.His250_Phe251del	Saglam et al. 2017	perinatal	c.[799_804del];[799_804del]					na
8	c.809G>A	p.Trp270*	P	Trp253*	Mornet et al. 1998 del Angel et al. 2020 del Angel et al. 2020	perinatal perinatal adult	c.[809G>A];[550C>T] c.[809G>A];[1228T>C] c.[809G>A];[=]	1.2	Zurutuza et al. 1999			na
8	c.814C>T	p.Arg272Cys	P	Arg255Cys	Spentchian et al. 2006	perinatal	c.[814C>T];[400_401delinsCA]	6.7	del Angel et al. 2020	79.6	del Angel et al. 2020	++
8	c.814del	p.Arg272Alafs		Arg255Alafs	Versailles lab June 2011 del Angel et al. 2020 del Angel et al. 2020	perinatal adult	c.[814del];[1142A>G] c.[814del];[=]					na
8	c.815G>T	p.Arg272Leu	P	Arg255Leu	Spentchian et al. 2003	perinatal	c.[815G>T];[662del]	33.7	del Angel et al. 2020	55.4	del Angel et al. 2020	++
8	c.815G>A	p.Arg272His	P	Arg255His	Brun-Heath et al. 2005 del Angel et al. 2020 Mornet et al. 2020	infantile odonto adult	c.[815G>A];[815G>A] c.[815G>A];[=] c.[815G>A];[=]	6.8 43.7	Brun-Heath et al. 2005 del Angel et al. 2020	89.9	del Angel et al. 2020	++
8	c.824T>C	p.Leu275Pro	P	Leu258Pro	Orimo et al. 2002	childhood	c.[824T>C];[529G>A]	3.3	Orimo et al. 2001			++
8	c.841del	p.His281Thrfs		His264Thrfs	Clinvar (Counsyl)	infantile	not provided					na
8	c.850_853dupGACT	p.Tyr285*		Tyr268*	Michigami et al. 2005	perinatal	c.[850_853dupGACT];[1559del]					na
IVS8	c.862+5G>A		P		Taillandier et al. 1999	infantile	c.[862+5G>A];[862+5G>A]					na

9	c.865C>T	p.Leu289Phe	P	Leu272Phe	Sugimoto et al. 1998	infantile	c.[865C>T];[1559del]	50	Sugimoto et al. 1998			++
9	c.868_869del	p.Phe290fs	LP	Phe273fs	Versailles lab Sept 2019	adult	c.[868_869del];[=]					na
9	c.871G>A	p.Glu291Lys	P	Glu274Lys	Mornet et al. 1998	infantile	c.[571G>A];[871G>A]	8.3 3.9	Zurutuza et al. 1999 del Angel et al. 2020	79.2	del Angel et al. 2020	++
9	c.871G>T	p.Glu291*	P	Glu274Ter	Taillandier et al. 2000 Mornet et al. 2020	perinatal perinatal	c.[871G>T];[331G>A] c.[871G>T];[385G>A]	3.2	del Angel et al. 2020	61.0	del Angel et al. 2020	na
9	c.871G>C	p.Glu291Gln		Glu274Gln	Versailles lab Jun 2010	perinatal	c.[871G>C];[871G>C]	41.5	del Angel et al. 2020	92.0	del Angel et al. 2020	++
9	c.874C>A	p.Pro292Thr	P	Pro275Thr	Brun-Heath et al. 2005	infantile	c.[98C>T];[874C>A]	4.0 63.5	Brun-Heath et al. 2005 del Angel et al. 2020	89.2	del Angel et al. 2020	++
9	c.874C>T	p.Pro292Ser	P	Pro275Ser	Tenorio et al. 2017		c.[815G>T];[874C>T]					++
9	c.875_881delinsT	p.Gly293_Asp294del	P	Gly276_Asp277del	Belachew et al. 2013 Prevention Genetics	perinatal childhood severe	c.[875_881delinsT];[1559del] c.[875_881delinsT];[=]					na
9	c.876_881del	p.Gly293_Asp294del	P	Gly276_Asp277del	Spentchian et al. 2003	perinatal	c.[876_881del];[963del]					na
9	c.880G>T	p.Asp294Tyr	P	Asp277Tyr	Taillandier et al. 2001	infantile	c.[880G>T];[526G>A]					++
9	c.881A>C	p.Asp294Ala	P	Asp277Ala	Henthorn et al. 1992 Mumm et al. 2002 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	infantile infantile infantile adult infantile perinatal	c.[881A>C];[211C>T] c.[881A>C];[668G>A] c.[881A>C];[979T>C] c.[881A>C];[571G>A] c.[881A>C];[547G>C] c.[881A>C];[1553_1559del]	35 8.9	Fukushi-Irié et al. 2000 del Angel et al. 2020	89.2 89.2	del Angel et al. 2020	++
9	c.883A>G	p.Met295Val	P	Met278Val	Mornet et al. 2001	childhood	c.[883A>G];[571G>A]					+
9	c.884T>C	p.Met295Thr	P	Met278Thr	Brun-Heath et al. 2005 del Angel et al. 2020	perinatal adult	c.[884T>C;[667C>T] c.[884T>C];[400_401delinsCA]	8.5 22.7	Brun-Heath et al. 2005 del Angel et al. 2020	95.3	del Angel et al. 2020	+
9	c.885G>A	p.Met295Ile	P	Met278Ile	Michigami et al. 2005	perinatal	c.[885G>A];[1559del]					+
9	c.886C>T	p.Gln296*		Gln279*	Plendl et al. 2011	adult	c.[886C>T];[?]					na
9	c.889T>G	p.Tyr297Asp	P	Tyr280Asp	Brun-Heath et al. 2005	childhood	c.[407G>A];[889T>G]	1.3	Brun-Heath et al. 2005			++
9	c.889T>C	p.Tyr297His	P	Tyr280His	Bertola et al. 2009	perinatal	c.[648+1G>A];[889T>C]					++
9	c.889T>A	p.Tyr297Asn		Tyr280Asn	Research center for medical genetics, Moscow, Oct. 2015	childhood	c.[889T>A];[?]					++
9	c.891C>G	p.Tyr297*	P	Tyr280*	Versailles lab March 2020	adult	c.[891C>G];[=]					na
9	c.891C>A	p.Tyr297*	P	Tyr280*	Balasubramaniam et al. 2010	infantile	c.[891C>A];[1471G>A]	2.8	del Angel et al. 2020	62.3	del Angel et al. 2020	na
9	c.892G>A	p.Glu298Lys	P	Glu281Lys	Orimo et al. 1994	infantile	c.[892G>A];[1559del]	23.7	del Angel et al. 2020	90.7	del Angel et al. 2020	++
9	c.896T>C	p.Leu299Pro	P	Leu282Pro	Versailles lab oct. 2003 del Angel et al. 2020	infantile odonto	c.[896T>C];[896T>C] c.[896T>C];[=]	9.7 38.2	Michigami et al. 2005 del Angel et al. 2020	96.7	del Angel et al. 2020	++
9	c.901A>T	p.Arg301Trp	LP	Arg284Trp	Alonso et al. 2019	adult with unspecific signs (osteoporosis)	c.[901A>T];[=]					++
9	c.902del	p.Asn302Thrfs		p.Asn285Thrfs	Research center for medical genetics, Moscow, Nov. 2016	childhood	c.[902del];[?]					na
9	c.917A>T	p.Asp306Val	P	Asp289Val	Taillandier et al. 1999	infantile	c.[917A>T];[917A>T]	0 3.4	Ishida et al. 2003 del Angel et al. 2020	57.1	del Angel et al. 2020	++
9	c.919C>T	p.Pro307Ser	P	Pro290Val	Versailles lab oct. 2004	infantile	c.[919C>T];[1400T>C]					++
9	c.920C>T	p.Pro307Leu	LP	Pro290Leu	Versailles lab Jul. 2006 Alonso et al. 2019 del Angel et al. 2020	childhood adult with unspecific signs (osteoporosis) infantile	c.[920C>T];[542C>T] c.[920C>T];[=] c.[920C>T];[=]	5.3	del Angel et al. 2020	89.9	del Angel et al. 2020	++
9	c.928_929del	p.Ser310Argfs	P	Ser293Argfs	Brun-Heath et al. 2005	perinatal	c.[928_929del];[1231A>G]					na
9	c.931G>A	p.Glu311Lys	P	Glu294Lys	Spentchian et al. 2003	perinatal	c.[931G>A];[389_392del]	3.9	del Angel et al. 2020	77.9	del Angel et al. 2020	++
9	c.952C>T	p.Gln318*		Gln301*	Versailles lab Dec 2011	perinatal	c.[952C>T];[1216G>A]					na
9	c.963del	p.Lys322Argfs	P	Lys305Argfs	Spentchian et al. 2003	perinatal	c.[876_881del];[963del]					na
9	c.968A>T	p.Asn323Ile		Asn306Ile	City Hospital #40, St Petersburg, Russia	childhood	c.[968A>T];[?]					++
9	c.969C>G	p.Asn323Lys		Asn306Lys	Versailles lab oct. 2009	childhood	c.[648+1G>A];[969C>G]					++
9	c.976G>C	p.Gly326Arg	P	Gly309Arg	Litmanovitz et al. 2002	perinatal	c.[976G>C];[871G>A]]					++
9	c.977G>T	p.Gly326Val	P	Gly309Val	Versailles lab Jul 2008	perinatal	c.[977G>T];[977G>T]					++
9	c.980T>G	p.Phe327Cys	P	Phe310Cys	Mornet et al. 2001 McKiernan et al.2017	perinatal asymptomatic*	c.[401C>A];[980T>G] c.[980T>G];[=]					++
9	c.979_980delinsGG	p.Phe327Gly	P	Phe310Gly	Taillandier et al. 2001	adult	c.[571G>A];[979_980delinsGG]					++
9	c.979T>C	p.Phe327Leu	P	Phe310Leu	Ozono et al. 1996 Mao et al.2019 Michigami et al.2020	infantile odonto odonto	c.[979T>C];[1366G>A] c.[979T>C];[1017dupG] c.[979T>C];[1559del]	72 97.5	Cai et al. 1998 del Angel et al. 2020	1.24	del Angel et al. 2020	++
9	c.982T>C	p.Phe328Leu	P	Phe311Leu	Michigami et al. 2005	perinatal benign	c.[299C>T];[982T>C]	10	Michigami et al. 2005			++
9	c.984_986del	p.Phe328del	P	Phe311del	Orimo et al. 1997 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	infantile perinatal childhood perinatal adult childhood	c.[984_986del];[1559del] c.[984_986del];[1460C>T] c.[984_986del];[571G>A] c.[984_986del];[648+5G>C] c.[984_986del];[=] c.[984_986del];[=]	10 4.5	Michigami et al. 2005 del Angel et al. 2020	70.4	del Angel et al. 2020	na
IVS9	c.997+1G>T		P		Liu et al. 2010	odonto	c.[997+1G>T];[1162T>C]					na
IVS9	c.997+2T>A		P		Taillandier et al. 2000	perinatal	c.[997+2T>A];[1466G>C]					na
IVS9	c.997+2T>G		P		Brun-Heath et al. 2005	perinatal	c.[997+2T>G];[997+2T>G]					na
IVS9	c.997+3A>C		P		Mornet et al. 1998	perinatal	c.[997+3A>C];[997+3A>C]					na
IVS9	c.997+3A>G		P		Wenkert et al. 2011	prenatal benign	c.[997+3A>G];[1181_1182del]					na
IVS9	c.998-2A>G				Clinvar (Counsyl)	infantile	not provided					na
IVS9	c.998-1G>T		P		Taillandier et al. 2001	perinatal	c.[571G>A];[998-1G>T]					na

10	c.1000G>C	p.Gly334Arg	P	Gly317Arg	Fauvert et al. 2009	odonto	c.[1000G>C];[=]	5.0	Fauvert et al. 2009	39.0	Fauvert et al. 2009	++
10	c.1001G>A	p.Gly334Asp	P	Gly317Asp	Greenberg et al. 1993 Hofmann et al.2014 del Angel et al. 2020 del Angel et al. 2020 Rolvien et al. 2019	perinatal childhood perinatal odonto infantile	c.[1001G>A];[1001G>A] c.[1001G>A];[571G>A] c.[1001G>A];[1444dup] c.[1001G>A];[=] c.[1001G>A];[=]	0 6.5	Fukushi et al. 1998 del Angel et al. 2020	40.0 28.3	Fauvert et al. 2009 del Angel et al. 2020	++
10	c.1004G>C	p.Arg335Thr		Arg318Thr	Institute of Human Genetics, UK Hamburg-Eppendorf, Germany	adult	c.[1004G>C];[=]	6.0	del Angel et al. 2020	47.5	del Angel et al. 2020	++
10	c.1010A>G	p.Asp337Gly	P	Asp320Gly	Whyte et al. 2015	childhood	c.[571G>A];[1010A>G]	4.1	del Angel et al. 2020	32.1	del Angel et al. 2020	++
10	c.1015G>A	p.Gly339Arg		Gly322Arg	Mumm et al. 2002	perinatal	c.[526G>A];[1015G>A]	1.1 3.7	Fauvert et al. 2009 del Angel et al. 2020	33.0 45.8	Fauvert et al. 2009 del Angel et al. 2020	++
10	c.1015G>C	p.Gly339Arg	P	Gly322Arg	Schalin-Jantti et al. 2010 del Angel et al. 2020	adult odonto	[1015G>C];[571G>A] c.[1015G>C];[=]					++
10	c.1016G>A	p.Gly339Glu	P	Gly322Glu	Versailles lab oct. 2004	infantile	c.[382G>A];[1016G>A]					++
10	c.1017dup	p.His340Alafs	P	p.His323Alafs	Mao et al.2019	odonto	c.[979T>C];[1017dup]					na
10	c.1022A>G	p.His341Arg	P	His324Arg	Versailles lab Dec. 2018	prenatal benign (likely)	c.[1022A>G];[?]	4.4	del Angel et al. 2020	37.8	del Angel et al. 2020	++
10	c.1039C>T	p.Gln347*	P	Gln330*	Park et al. 2016	infantile	c.[334G>A];[1039C>T]					na
10	c.1042G>A	p.Ala348Thr	P	Ala331Thr	Taillandier et al. 2000	infantile	c.[571G>A];[1042G>A]	33.2	Taillandier et al. 2000			++
10	c.1044_1055del	p.Leu349_Ala352del	P	Leu332_Ala335del	Spentchian et al. 2006	perinatal	c.[1044_1055del];[1471G>A]					na
10	c.1062G>C	p.Glu354Asp	P	Glu337Asp	Souka et al. 2002	perinatal	c.[634A>T];[1062G>C]					++
10	c.1064T>C	p.Met355Thr	P	Met338Thr	Versailles lab oct. 2004	perinatal	c.[662G>T];[1064T>C]					++
10	c.1065G>A	p.Met355Ile	P	Met338Ile	Versailles lab. Jan. 2008	infantile	c.[1065G>A];[1171C>T]					++
10	c.1068C>G	p.Asp356Glu	VUS	Asp339Glu	McKiernan et al.2017	asymptomatic*	c.[1068C>G];[=]
10	c.1068C>A	p.Asp356Glu	VUS	Asp339Glu	Versailles lab Apr 2011	perinatal	c.[668G>A];[1068C>A]					++
10	c.1070G>T	p.Arg357Leu		Arg340Leu	Nielson et al. 2012	asymptomatic*, low BMD	c.[1070G>T];[?]					+
10	c.1072G>A	p.Ala358Thr		Ala 341Thr	Research center for medical genetics, Moscow, Nov. 2015	adult	c.[1072G>A];[?]					++
10	c.1077C>G	p.Ile359Met	P	Ile342Met	Whyte et al. 2012	infantile	c.[1077C>G];[1133A>T]					++
10	c.1078_1081dup	p.Gln361Argfs	P	Gln344Argfs	Versailles lab, May 2020	adult	c.[1078_1081dup];[1417G>A]					na
10	c.1083_1084dup	p.Ser364Argfs		Ser347Argfs	Riancho-Zarrabeitia et al. 2016	asymtomatic* or very mild symptoms	c.[1083_1084dup];[?]					na
10	c.1088_1091dup	p.Ser364Argfs	P	Ser347Argfs	Clinvar (Counsyl)	infantile	not provided					na
10	c.1097C>A	p.Thr366Asn		Thr349Asn	Versailles lab march 2016	asymtomatic* or very mild symptoms	c.[1097C>A];[?]					++
10	c.1101_1103del	p.Ser368del	P	Ser351del	Versailles lab oct. 2004	perinatal	c.[1101_1103del];[1166C>T]					na
10	c.1112C>T	p.Thr371Ile	P	Thr354Ile	Baumgartner-Sigl et al. 2007	infantile	c.[677T>C];[1112C>T]					++
10	c.1120G>A	p.Val374Met	P	Val357Met	Versailles lab oct. 2004 Alonso et al. 2019	adult adult with unspecific signs (osteoporosis)	c.[892G>A];[1120G>A] c.[1120G>A];[=]	57.6 98.9	Zhu et al. 2012 del Angel et al. 2020	1.12	del Angel et al. 2020	+
10	c.1130C>T	p.Ala377Val	P	Ala360Val	Mornet et al. 2001 del Angel et al. 2020	perinatal Odonto	c.[1130C>T];[1130C>T] c.[1130C>T];[=]	0 2.3	Michigami et al.2020	50 54.2	Michigami et al.2020	++
10	c.1132G>T	p.Asp378Tyr		Asp361Tyr	del Angel et al. 2020	odonto.	c.[1132G>T];[=]	0	Michigami et al.2020		Michigami et al.2020	++
10	c.1132G>C	p.Asp378His	P	Asp361His	Whyte et al. 2015	childhood	c.[571G>A];[1132G>C]					++
10	c.1133A>T	p.Asp378Val	P	Asp361Val	Henthorn et al. 1992 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	infantile perinatal childhood Prenat. benign	c.[571G>A];[1133A>T] c.[1133A>T];[1133A>T] c.[1133A>T;[=] c.[1133A>T];[=]	1.2 2.1	Lia-Baldini et al. 2001 del Angel et al. 2020	19.9 28.2	Lia-Baldini et al. 2001 del Angel et al. 2020	++
10	c.1133A>G	p.Asp378Gly	P	Asp361Gly	Tenorio et al. 2017		c.[1133A>G];[571G>A]					++
10	c.1135C>A	p.His379Asn	P	His362Asn	Dr Ivan Iglesias-Baena, CEO GenActive Clinic & Research, C / Madrid 79, Monachil, 18193, Granada, Spain. info@genactive.es	adult	c.[1135C>A];[=]					++
10	c.1142A>G	p.His381Arg	P	His364Arg	Taillandier et al. 2000 del Angel et al. 2020	infantile perinatal	c.[1142A>G];[119C>T] c.[1142A>G];[814del]					++
10	c.1144G>A	p.Val382Ile	P	Val365Ile	Goseki-Sone et al. 1998 del Angel et al. 2020	childhood prenat. benign	c.[1144G>A];[979T>C] c.[1144G>A];[=]	0	Watanabe et al. 2002	30.0	Takinami et al. 2004	++
10	c.1162T>C	p.Tyr388His	P	Tyr371His	Liu et al. 2010 Yang et al. 2013	odonto odonto	c.[997+1G>T];[1162T>C] c.[82T>G];[1162T>C]	39.7	Zhu et al. 2012	60	Yang et al. 2013	++
10	c.1166C>T	p.Thr389Ile	P	Thr372Ile	Versailles lab oct. 2004	perinatal	c.[1101_1103del];[1166C>T]					++
10	c.1166C>A	p.Thr389Asn	P	Thr372Asn	Yang et al. 2013 Bai et al. 2016 Versailles lab Jan 2020	childhood perinatal perinatal	c.[1166C>A];[407G>T] c.[1166C>A];[1250A>G] c.[1166C>A];[1166C>A]	0	Yang et al. 2013	40	Yang et al. 2013	++
10	c.1171C>T	p.Arg391Cys	P	Arg374Cys	Zurutuza et al. 1999 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	childhood adult childhood infantile	c.[571G>A];[1171C>T] c.[1171C>T];[N] c.[1171C>T];[N] c.[1171C>T];[1042G>A]	10.3 2.2	Zurutuza et al. 1999 del Angel et al. 2020	50.5 55.2	Fauvert et al. 2009 del Angel et al. 2020	++
10	c.1172G>A	p.Arg391His	P	Arg374His	Orimo et al. 2002 del Angel et al. 2020	childhood adult	c.[1172G>A];[=] c.[1172G>A];[=]	3.7 2.1	Orimo et al. 2001 del Angel et al. 2020	29.1 20.4	Fauvert et al. 2009 del Angel et al. 2020	++
10	c.1171del	p.Arg391Valfs	P	Arg374Valfs	Taillandier et al. 1999 del Angel et al. 2020 del Angel et al. 2020	infantile infantile infantile	c.[184A>T];[1171del] c.[1171del];[1171del] c.[1171del];[571G>A]	2.1	del Angel et al. 2020	72.9	del Angel et al. 2020	na
10	c.1175G>C	p.Gly392Ala	P	Gly375Ala	Versailles lab. Jan. 2008	perinatal	c.[1175G>C];[406C>T]					++
10	c.1178A>T	p.Asn393Ile		Asn376Ile	Versailles lab March 2013	infantile moderate	c.[571G>A];[1178A>T]					+
10	c.1181_1182del	p.Ser394fs	P	Ser377fs	Wenkert et al. 2011	prenatal benign	c.[997+3A>G];[1181_1182del]					na
10	c.1182dup	p.Ile395fs		Ile395fs	communicated by Dr Rhonda Singhapong (Alexion)	adult	c.[1182dup] ;[=]					na
10	c.1183A>G	p.Ile395Val	P	Ile378Val	Wenkert et al. 2011 Katsuyuki et al. 2019 Mornet et al. 2020	prenatal benign childhood adult	c.[1183A>G];[457T>C] c.[1183A>G];[1559del] c.[1183A>G];[=]	19	Chen et al. 2017	50	Chen et al. 2017	++
10	c.1184T>C	p.Ile395Thr	P	Ile378Thr	Versailles lab Jul. 2006	perinatal	c.[1184T>C];[571G>A]					++
IVS10	c.1189+5del		P		Whyte et al. 2015	childhood	c.[1189+5del];[1328C>T]					na

11	c.1190G>A	p.Gly397Asp	P	Gly380Asp	Whyte et al. 2015	odonto.	c.[1190G>A];[=]					++
11	c.1190G>T	p.Gly397Val		Gly380Asp	Versailles lab Dec. 2019	childhood (moderate)	c.[1190G>T];[=]					++
11	c.1195G>T	p.Ala399Ser	P	Ala382Ser	Taillandier et al. 2001	adult	c.[1195G>T];[704A>G]					++
11	c.1196C>T	p.Ala399Val	P	Ala382Val	Spentchian et al. 2006 del Angel et al. 2020	adult perinatal	c.[1196C>T];[98C>T] c.[1196C>T];[648+2dup]					++
11	c.1199C>T	p.Pro400Leu	P	Pro383Leu	Spentchian et al. 2006	infantile	c.[1199C>T];[1199C>T]					++
11	c.1214_1215del	p.Thr405Argfs	P	Thr388Argfs	Versailles lab Jul. 2006	adult	c.[571G>A];[1214_1215del]					na
11	c.1216_1219del	p.Asp406Argfs	P	Asp389Argfs	Brun-Heath et al. 2005	perinatal	c.[1216_1219del];[?]					na
11	c.1216G>A	p.Asp406Asn		Asp389Asn	Versailles lab Dec 2011	perinatal	c.[952C>T];[1216G>A]					-
11	c.1217A>G	p.Asp406Gly	P	Asp389Gly	Taillandier et al. 2000	odonto.	c.[1217A>G];[1349G>A]	14.9	Taillandier et al. 2000			-
11	c.1228T>C	p.Phe410Leu	P	Phe393Leu	Versailles lab oct. 2004	infantile	c.[1228T>C];[571G>A]					+
11	c.1231A>G	p.Thr411Ala	P	Thr394Ala	Brun-Heath et al. 2005	perinatal	c.[1231A>G];[928_929del]	0.3	Brun-Heath et al. 2005			++
11	c.1238T>C	p.Ile413Thr		p.Ile396Thr	University of Brasilia Lab, July 2016	childhood	c.[1238T>C];[?]					++
11	c.1240C>A	p.Leu414Met	P	Leu397Met	Mumm et al. 2002	perinatal	c.[1240C>A];[811A>C] c.[1240C>A];[=]	0.4 5.1	Fauvert et al. 2009 del Angel et al. 2020	23.5 43.7	Fauvert et al. 2009 del Angel et al. 2020	++
11	c.1243T>G	p.Tyr415Asp		Tyr398Asp	Saglam et al. 2017	perinatal	c.[1243T>G];[1243T>G]					++
11	c.1244A>G	p.Tyr415Cys	LP	Tyr398Cys	Versailles lab March 2020	adult	c.[1244A>G];[=]					++
11	c.1250A>G	p.Asn417Ser	P	Asn400Ser	Sergi et al. 2001 Reibet et al. 2009 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	perinatal odonto adult childhood prenat benign	c.[1250A>G];[648+1G>A] c.[1250A>G];[=] c.[1250A>G];[=] c.[1250A>G];[=] c.[1250A>G];[=]	3 3.6	Fauvert et al. 2009 del Angel et al. 2020	26.5 31.9	Fauvert et al. 2009 del Angel et al. 2020	++
11	c.1256del	p.Pro419Leufs	P	Pro402Leufs	Taillandier et al. 2000	perinatal	c.[1256del];[?]					na
11	c.1258G>A	p.Gly420Ser	P	Gly403Ser	Glaser et al. 2004 del Angel et al. 2020	perinatal perinatal	c.[1258G>A];[1258G>A] c.[1258G>A];[299C>T]	0 3.7	Makita et al. 2012 del Angel et al. 2020	40 31.1	Makita et al. 2012 del Angel et al. 2020	++
11	c.1259G>C	p.Gly420Ala	P	Gly403Ala	Fauvert et al. 2009 del Angel et al. 2020	childhood odonto	c.[1259G>C];[571G>A] c.[1259G>C];[=]	4.2	Fauvert et al. 2009	19.7	Fauvert et al. 2009	++
11	c.1259G>A	p.Gly420Asp		Gly403Asp	Versailles lab Feb. 2019 del Angel et al. 2020	childhood childhood	c.[1259G>A];[=] c.[1259G>A];[407G>A]	4.0	del Angel et al. 2020	34.3	del Angel et al. 2020	++
11	c.1265A>G	p.Lys422Arg		Lys405Arg	Versailles lab April 2018	adult	c.[1265A>G];[=]	78.7	del Angel et al. 2020	80.5	del Angel et al. 2020	+
11	c.1268T>C	p.Val423Ala	P	Val406Ala	Taillandier et al. 2001 del Angel et al. 2020	perinatal childhood	c.[1268T>C];[346G>A] c.[1268T>C];[=]	15.7	Numa et al. 2008			+
11	c.1270G>A	p.Val424Met	P	Val407Met	Versailles lab jan. 2007	adult	c.[1270G>A];[1270G>A]	58.5	del Angel et al. 2020	88.4	del Angel et al. 2020	+
11	c.1271T>C	p.Val424Ala	P	Val407Ala	Zhang et al. 2012	adult	c.[1271T>C];[1271T>C]					+
11	c.1276G>T	p.Gly426Cys	P	Gly409Cys	Mochizuki et al. 2000	infantile	c.[670A>G];[1276G>T]	18.5	Michigami et al. 2005			++
11	c.1276G>A	p.Gly426Ser	P	Gly409Ser	Versailles lab Apr 2011 Mornet et al. 2020	infantile adult	c.[1276G>A];[1276G>A] c.[1276G>A];[=]	10	Al-Shawafi et al. 2016	50	Al-Shawafi et al. 2016	++
11	c.1277G>A	p.Gly426Asp	P	Gly409Asp	Mumm et al. 2002	childhood	c.[571G>A];[1277G>A]	0	Al-Shawafi et al. 2016	60	Al-Shawafi et al. 2016	++
11	c.1282C>T	p.Arg428*	P	Arg411Ter	Taillandier et al. 1999	perinatal	c.[1282C>T];[1282C>T]	3.3	del Angel et al. 2020	68.9	del Angel et al. 2020	na
11	c.1283G>C	p.Arg428Pro	P	Arg411Pro	Spentchian et al. 2006	perinatal	c.[997+2T>A];[1283G>C]					++
11	c.1283G>A	p.Arg428Gln		Arg411Gln	Versailles lab Jul. 2010 del Angel et al. 2020	prenatal benign childhood	c.[1283G>A];[=] c.[1283G>A];[=]	4.2	del Angel et al. 2020	48.5	del Angel et al. 2020	++
11	c.1283G>T	p.Arg428Leu		Arg411Leu	Plendl et al. 2011	adult	c.[1283G>T];[?]					++
11	c.1285G>A	p.Glu429Lys	P	Glu412Lys	Versailles lab Jul. 2006	odonto.	c.[1285G>A];[=]	1.3	Fauvert et al. 2009	31.0	Fauvert et al. 2009	++
11	c.1289A>G	p.Asn430Ser	P	Asn413Ser	Whyte et al. 2015	infantile	c.[571G>A];[1289A>G]	0	Komaru et al. 2016	58	Komaru et al. 2016	++
11	c.1292T>A	p.Val431Asp	LP	Val414Asp	Esmel-Vilomara et al. 2019	childhood HPP (diagnosed at birth)	c.[1292T>A];[=]					+
11	c.1292T>C	p.Val431Ala	P	Val414Ala	Taillandier et al. 2015	odonto.	c.[1292T>C];[=]					+
11	c.1306T>C	p.Tyr436His	P	Tyr419His	Henthorn et al. 1992	childhood	c.[98C>T];[1306T>C]					++
11	c.1307A>G	p.Tyr436Cys	P	Tyr419Cys	Taketani et al. 2013	infantile	c.[1307A>G];[1559del]					++
11	c.1307A>C	p.Tyr436Ser		Tyr419Ser	Nielson et al. 2012	asymptomatic*, low BMD	c.[1307A>C];[=]					++

12	c.1313A>T	p.His438Leu	P	His421Leu	del Angel et al. 2020	perinatal survival	c[.1313A>T];[1313A>T]					++
12	c.1318_1320 del	p.Asn440del	P	Asn423del	Martins et al. 2013	odonto.	c.[454C>T];[1318_1320del]					na
12	c.1323C>A	p.Tyr441*	P	Tyr424*	Hofmann et al. 2013	perinatal	c.[667C>T];[1323C>A]	1.0	Hofmann et al. 2013	58.3	Hofmann et al. 2013	na
12	c.1327G>A	p.Ala443Thr		Ala426Thr	Garcia-Fontana et al. 2019	Adult	c.[1327G>A];[=]	7.0	del Angel et al. 2020	72.9	del Angel et al. 2020	++
12	c.1328C>T	p.Ala443Val	P	Ala426Val	Fauvert et al. 2009 Mornet et al 2020	adult childhood	c.[1328C>T];[=] c.[1328C>T];[=]	1.4 7.7	Fauvert et al. 2009 del Angel et al. 2020	53.1 57.4	Fauvert et al. 2009 del Angel et al. 2020	++
12	c.1328C>A	p.Ala443Glu	P	Ala426Glu	Khandwala et al. 2006	adult	c.[1328C>A];[=]					++
12	c.1333T>C	p.Ser445Pro	P12	Ser428Pro	Mornet et al. 1998 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020	infantile infantile adult odonto	c.[1333T>C];[?] c.[1333T>C];[407G>A] c.[1333T>C];[=] c.[1333T>C];[=]	2.1	Zurutuza et al. 1999	35.1	Fauvert et al. 2009	+
12	c.1336G>A	p.Ala446Thr	P	Ala429Thr	Versailles lab Jan 2013	perinatal	c.[1336G>A];[1336G>A]					++
12	c.1348C>T	p.Arg450Cys	P	Arg433Cys	Mornet et al. 1998 del Angel et al. 2020	infantile perinatal	c.[1348C>T];[1348C>T] c.[1348C>T];[1348C>T]	4.0 11.2	Zurutuza et al. 1999 del Angel et al. 2020	101	del Angel et al. 2020	+
12	c.1349G>A	p.Arg450His	P	Arg433His	Taillandier et al. 2000	odonto.	c.[1217A>G];[1349G>A]
12	c.1354G>A	p.Glu452Lys	P	Glu435Lys	Spentchian et al. 2003 del Angel et al. 2020	perinatal adult	c.[1354G>A];[331G>A] c.[1354G>A];[=]	1.4 4.1	Fauvert et al. 2009 del Angel et al. 2020	27.5 32.3	Fauvert et al. 2009 del Angel et al. 2020	++
12	c.1361A>G	p.His454Arg	P	His437Arg	Versailles lab oct. 2003	childhood	c.[571G>A];[1361A>G]	2.4	del Angel et al. 2020	36.9	del Angel et al. 2020	++
12	c.1363G>A	p.Gly455Ser	P	Gly438Ser	Draguet et al. 2004	adult	c.[1363G>A];[1471G>A]	71.0 1.19	Brun-Heath et al. 2007 del Angel et al. 2020	1.19	del Angel et al. 2020	++
12	c.1364G>A	p.Gly455Asp	P	Gly438Asp	Versailles lab jan. 2007	perinatal	c.[1364G>A];[1364G>A]					++
12	c.1366G>T	p.Gly456Trp	P	Gly439Trp	Versailles lab oct. 2003	childhood	c.[1366G>T];[?]	0.8	Fauvert et al. 2009	14.5	Fauvert et al. 2009	++
12	c.1366G>A	p.Gly456Arg		Gly439Arg	Ozono et al. 1996 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 Yokoi et al. 2019	infantile infantile childhood odonto mild/moderate	c.[1366G>A];[?] c.[1366G>A];[881A>C] c.[1366G>A];[=] c.[1366G>A];[=] c.[1366G>A];[=]	1.5 2.5	Fauvert et al. 2009 d del Angel et al. 2020	50.5 42.2	Fauvert et al. 2009 del Angel et al. 2020	++
12	c.1367G>A	p.Gly456Glu		Gly439Glu	Versailles lab. Dec 2018	Odonto childhood	c.[1367G>A];[=]	4.8	del Angel et al. 2020	30.9	del Angel et al. 2020	++
12	c.1372G>A	p.Asp458Asn		Asp441Asn	Versailles lab Dec 2011	adult	c.[571G>A];[372G>A]					++
12	c.1373A>G	p.Asp458Gly		Asp441Gly	Plendl et al. 2011	infantile	c.[571G>A];[1373A>G]					++
12	c.1375G>A	p.Val459Met	P	Val442Met	Taillandier et al. 2000 Whyte et al. 2016	infantile infantile	c.[152C>T];[1375G>A] c.[252G>C];[1375G>A]					++
12	c.1375G>T	p.Val459Leu	P	Val442Leu	Versailles lab oct. 2004	perinatal odonto	c.[1354G>A];[1375G>T] c[1375G>T];[=]	0	Fauvert et al. 2009	41.1	Fauvert et al. 2009	++
12	c.1376T>C	p.Val459Ala		Val442Ala	Xu et al. 2018	adult	c.[1376T>C];[=]					++
12	c.1381G>A	p.Val461Ile	LP	Val444Ile	Nielson et al. 2012 del Angel et al. 2020	asymptomatic*, low BMD adult	c.[1381G>A];[?] c.[1381G>A];[=]	80.1	del Angel et al. 2020	89.0	del Angel et al. 2020	+
12	c.1397C>T	p.Pro466Leu	P	Pro449Leu	Versailles lab oct. 2003	perinatal	c.[1397C>T];[?]	5.7	del Angel et al. 2020	51.8	del Angel et al. 2020	+
12	c.1400T>C	p.Met467Thr	P	Met450Thr	Versailles lab oct. 2004	infantile	c.[919C>T];[1400T>C]					+
12	c.1402G>A	p.Ala468Thr	P	Ala451Thr	Spentchian et al. 2003 del Angel et al. 2020	perinatal infantile	c.[1402G>A];[1402G>A] c.[1402G>A];[1402G>A]	5.6	del Angel et al. 2020	78.7	del Angel et al. 2020	++
12	c.1403C>T	p.Ala468Val		Ala451Val	Taillandier et al. 2017	adult	c.[1403C>T];[=]	3.9	del Angel et al. 2020	64.9	del Angel et al. 2020	++
12	c.1412_1429del	p.Leu471_Glu476del		Leu454_Glu459del	Plendl et al. 2011	adult	c.[1412_1429del];[?]					na
12	c.1414C>T	p.His472Tyr		His455Tyr	V. Buzzi, P. La Verde, Milan, Italy	perinatal	c.[299C>T];[1414C>T]					++
12	c.1417G>A	p.Gly473Ser	P	Gly456Ser	Mornet et al. 1998 Martins et al. 2019	perinatal adult	c.[1417G>A];[119C>T] c.[1417G>A];[1460C>T]					++
12	c.1418G>A	p.Gly473Asp		Gly456Asp	Nakamura-Utsunomiya et al. 2010	perinatal	c.[1418G>A];[1559del]					++
12	c.1418_1438dup	p.Gly473_Tyr479dup	LP	Gly456_Tyr62dup	Versailles lab Dec. 2019	asymptomatic	c.[1418_1438dup];[=]					na
12	c.1426G>A	p.Glu476Lys	P	Glu459Lys	Taillandier et al. 1999 del Angel et al. 2020 del Angel et al. 2020	perinatal infantile adult	c.[1426G>A];[331G>A] c.[1426G>A];[571G>A] c.[1426G>A];[=]	4.3	del Angel et al. 2020	37.5	del Angel et al. 2020	++
12	c.1426G>T	p.Glu476*		Glu459*	Clinvar (Counsyl)	infantile	not provided					++
12	c.1427A>G	p.Glu476Gly	P	Glu459Gly	Mornet et al. 2001	perinatal	c.[1427A>G];[1427A>G]					++
12	c.1427A>C	p.Glu476Ala	P	Glu459Ala	Versailles lab March 2009	adult	c.[1427A>C];[?]	0.4	Fauvert et al. 2009	39.3	Fauvert et al. 2009	++
12	c.1433A>T	p.Asn478Ile	P	Asn461Ile	Taillandier et al. 2000 del Angel et al. 2020	childhood odonto	c.[1433A>T];[=] c.[1433A>T];[=]	1.1	Lia-Baldini et al. 2001	38.2	Lia-Baldini et al. 2001	++
12	c.1444C>A	p.His482Asn	P	His465Asn	Nielson et al. 2012	asymptomatic*, low BMD	c.[1444C>A];[=]	91.8	del Angel et al. 2020	108	del Angel et al. 2020	++
12	c.1444dup	p.His482Profs		His465Profs	Brun-Heath et al. 2005	perinatal	c.[1444dup];[1001G>A]					na
12	c.1447G>A	p.Val483Met		Val466Met	Research center for medical genetics, Moscow, Aug. 2016	childhood	c.[1447G>A];[?]					+
12	c.1460C>T	p.Ala487Val	P	Ala470Val	Taillandier et al. 2015 Martins et al. 2019	perinatal adult	c.[1460C>T];[.984_986del] c.[1417C>T];[1460C>T]					++
12	c.1466G>C	p.Cys489Ser	P	Cys472Ser	Taillandier et al. 2000	perinatal	c.[997+2T>A];[1466G>C]	9.4 6.8	Taillandier et al. 2000 del Angel et al. 2020	58.4	del Angel et al. 2020	++
12	c.1468A>T	p.Ile490Phe	P	Ile473Phe	Lia-Baldini et al. 2001	adult	c.[1468A>T];[?]	37.1	Lia-Baldini et al. 2001	77.4	Lia-Baldini et al. 2001	+
12	c.1471G>A	p.Gly491Arg	P	Gly474Arg	Mornet et al. 1998 del Angel et al. 2020 del Angel et al. 2020 del Angel et al. 2020 Mornet et al. 2020 Yokoi et al. 2019	perinatal perinatal perinatal perinatal adult mild/moderate	c.[1471G>A];[385G>A] c.[1471G>A];[1471G>A] c.[1471G>A];[203C>T] c.[1471G>A];[303_311del] c.[1471G>A];[=] c.[1471G>A];[c.283G>A]	7.8	del Angel et al. 2020	72.8	del Angel et al. 2020	++
12	c.1474del	p.Ala492Profs	P	Ala475Profs	Brun-Heath et al. 2005 Galeano-Valle et al. 2019 del Angel et al. 2020	odonto adult perinatal	c.[1474del];[407G>A] c.[1474del];[=] c.[1474del];[668G>A]					na
12	c.1479C>A	p.Asn493Lys	P	Asn476Lys	Porntaveetus et al. 2017	infantile	c.[1460C>T];[1479C>A]					-
12	c.1483G>A	p.Gly495Ser	VUS	Gly478Ser	Michigami et al.2020	infantile	c.[1483G>A];[1483G>A]	72.5	del Angel et al. 2020	80.0	del Angel et al. 2020	-
12	c.1489T>A	p.Cys497Ser		Cys480Ser	Xu et al. 2018	adult	c.[1489T>A];[=]					++
12	c.1530_1549del	p.Leu512Profs		Leu495Profs	Clinvar (Counsyl)	infantile	not provided					na
12	c.1540G>A	p.Ala514Thr	VUS	Ala497Thr	Tenorio et al. 2017	infantile	c.[1540G>A];[407G>A]	96.2	del Angel et al. 2020	94.8	del Angel et al. 2020	+
12	c.1553_1569del	p.Tyr518Phefs		Tyr501Phefs	Versailles lab nov. 2009	perinatal	c.[1553_1569del];[881A>C]					na
12	c.1554C>A	p.Tyr518*		Tyr501*	Dr S. Monnot, Necker Hospital, Paris, France, Feb. 2019	perinatal	c.[1554C>A];[1554C>A]	6.0	del Angel et al. 2020	60.2	del Angel et al. 2020	na
12	c.1559del	p.Leu520Argfs	P	Leu503Argfs	Orimo et al. 1994 Yokoi et al. 2019 Michigami et al.2020 Michigami et al.2020 Michigami et al.2020 Michigami et al.2020 Michigami et al.2020	infantile odonto childhood perinatal severe perinatal benign odonto odonto odonto	c.[892G>A];[1559del] c.[1183A>G];[1559del] c.[1559del];[1559del] c.[572A>G];[1559del] c.[704A>T];[1559del] c.[407G>A];[1559del] c.[979T>C];[1559del]	28 5.6	Komaru et al. 2008 del Angel et al. 2020	82.2	del Angel et al. 2020	na
12	c.*124_126delinsAG		VUS		Versailles lab Sept 2019	adult	c.[124_126delinsAG]					na
Large deletions/duplications Due to the incertainty of borders, all large deletions/duplications submitted to the database will be included. However, each type will be counted only once.
deletion of exon 1					Versailles lab July 2012	perinatal	homozygote					na
3kb deletion in IVS1		g.(15599_18599)del			Versailles lab Oct. 2016	infantile	compound heterozygote with deletion exon 1 - IVS1 - exon 2					na
deletion exon 1 - IVS1 - exon 2		g.(1-54621_1-35638)_(44833_46877)del			Versailles lab May 2016	infantile	compound heterozygote with 3kb deletion in IVS1					na
deletion of exon 2		g.(16650_17870)_(48651_50859)del			Versailles lab July 2013	perinatal	homozygote					na
deletion of exon 2					H Mateus, Alexion Pharmaceuticals, Colombia	infantile	compound heterozygote with c.[382G>A]					na
deletion of exon 2		g.(42056_43422)_(46936_47669)del			Versailles lab Nov. 2018	adult	heterozygote					na
del IVS3					Whyte et al. 2015	odonto.	heterozygote					na
deletion exons 2-6					Dr I. Rau , Institut für Humangenetik, Hamburg, Germany	adult	heterozygote					na
duplication of exons 2-6			P		Hacihamdioglu et al. 2018	perinatal	homozygote					na
deletion of exons 3-5(?)		g.(44834_46878)_(51650_52773)del	P		Spentchian et al. 2006	perinatal	homozygote					na
indel in exon 5					Whyte et al. 2015	odonto.	heterozygote					na
deletion of exon 5					Versailles lab April 2018	adult	heterozygote					na
deletion exon 9		g.(?_64307)_(64441_?)del	P		Versailles lab Dec. 2015	prenat. benign	compound heterozygote with c.407G>A					na
deletion of exon 12 (3' part)			P		Spentchian et al. 2006	infantile	compound heterozygote with c.542C>T					na

* Phenotype "asymptomatic": repeatedly low serum alkaline phosphatase, no hypophosphatasia clinical symptom

Statistics

Type of mutation	Number of mutations	%
Missense	292	71.0
Small deletions	45	11.0
Splicing	20	4.9
Nonsense	20	4.9
Small insertions	14	3.4
Large del/dup	12	2.9
Ins/Del	6	1.5
Regulatory	2	0.5
Total	411	100

Legend to database items

Nomenclature : see the nomenclature section below.
Reference : reference of the publication reporting the mutation.
Pathogenicity: : classification of the variant according to Richards et al. (2015) and Karbassi et al. (2015). The classification give a score of pathogenicity : B benign; LB likely benign; VUS variant of unknown significance; LP likely pathogenic; P pathogenic
Clinical form : clinical form of the patient in whom the mutation was detected for the first time.
Genotype : genotype of the patient in whom the mutation was detected for the first time.
? : uncharacterized allele (only one detected mutation without molecular, pedigree, or in silico evidence of dominant transmission).
N : normal allele (dominant mutation on the other chromosome, evidenced by molecular, pedigree, or in silico data.
%WT : residual activity of the mutant protein. Alkaline phosphatase activity of cells transfected with mutant cDNAs, expressed in percentage of the activity found in cells transfected with wild type (WT) cDNA.
% 50/50 : dominant negative effect of the mutation. Alkaline phosphatase activity of cells co-transfected with equal quantities of wild type and mutant cDNAs, expressed in percentage of the activity found in cells transfected with wild type (WT) cDNA. For mutations producing no residual activity, the value is expected to be 50% if there is no dominant negative effect, and <50% if there is a dominant negative effect (Lia-Baldini et al. 2001).
unp. : unpublished.
Conservation : conservation of the affected amino acid among 58 mammalian TNSALP according to Silvent et al. (2014). ++ conserved residue ; + conservative changes only, - residue not conserved, na not applicable.

Nomenclature

Nucleotides numbering is given according to Weiss et al. 1988, the Nomenclature Working Group (S.E. Antonarakis and the Nomenclature Working Group, Hum. Mut. 11:1-3, 1998) and the HGVS recommendations: the first nucleotide (+1) corresponds to the A of the ATG initiation codon. Reference transcript: ENST00000374840.8 / NM_00478.6.)
Amino acids numbering is given according to both the standardized and the non-standardized nomenclatures.
The standardized nomenclature follows the HGVS recommendations: the first codon is the ATG initiation codon.
The non-standardized nomenclature was used in publications before 2008-2009 : this nomenclature takes into account of a 17-residues signal peptide, i.e. the ATG initiation codon is numbered as residue minus (-)17 (Weiss et al. 1988).
p: protein numbering; c: nucleotide numbering of the coding sequence.

References: