Submissions for variant NM_000169.3(GLA):c.1117G>A (p.Gly373Ser)

dbSNP: rs727504348

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000727357	SCV000707842	likely pathogenic	not provided	2018-06-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000154469	SCV000917447	pathogenic	Fabry disease	2022-08-05	criteria provided, single submitter	clinical testing	Variant summary: GLA c.1117G>A (p.Gly373Ser) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 183441 control chromosomes (gnomAD). c.1117G>A has been reported in the literature in multiple individuals affected with classic- or later onset Fabry Disease (e.g. Okumiya_1995, Thurberg_2017, Coutinho_2017, Kobayashi_2019, Bichet_2021) and also with hypertrophic cardiomyopathy (Alfares_2015, Walsh_2017). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated severely decreased enzyme activity (Okumiya_1995, Ishii_2007, Bichet_2021). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) / likely pathogenic (n=3). Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV000154469	SCV001141976	pathogenic	Fabry disease	2019-05-28	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000727357	SCV002018434	likely pathogenic	not provided	2020-08-17	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000154469	SCV002054372	likely pathogenic	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000844704	SCV000204138	likely pathogenic	Fabry disease; Hypertrophic cardiomyopathy	2013-02-11	no assertion criteria provided	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory