Submissions for variant NM_000169.3(GLA):c.8T>C (p.Leu3Pro)

gnomAD frequency: 0.00098  dbSNP: rs150547672

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035313	SCV000058961	benign	not specified	2015-07-29	criteria provided, single submitter	clinical testing	p.Leu3Pro in exon 1 of GLA: This variant is not expected to have clinical signif icance because it has been identified in 0.3% (26/8444) of African chromosomes i ncluding 4 hemizygous males by the Exome Aggregation Consortium (ExAC, http://ex ac.broadinstitute.org/; dbSNP rs150547672).
GeneDx	RCV000035313	SCV000207806	benign	not specified	2017-01-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000209748	SCV000296877	uncertain significance	Fabry disease	2015-10-13	criteria provided, single submitter	clinical testing
Invitae	RCV000209748	SCV000556167	likely benign	Fabry disease	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000622119	SCV000739986	likely benign	Cardiovascular phenotype	2018-09-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035313	SCV000917448	likely benign	not specified	2018-07-30	criteria provided, single submitter	clinical testing	Variant summary: GLA c.8T>C (p.Leu3Pro) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 200269 control chromosomes, predominantly observed within the African subpopulation at a frequency of 0.0029 in the gnomAD database, including 11 hemizygotes. This frequency is not higher than expected for a pathogenic variant in GLA causing Cardiomyopathy (0.0029 vs 0.0071). c.8T>C has been reported in the literature in individuals affected with Fabry disease (Lukas 2016), however in this study, authors found normal biomarker levels in these individuals. Experimental evidence evaluating an impact on protein function also showed normal (or somewhat elevated) activity for the variant protein (Lukas 2016). Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, with two laboratories classifying as "benign", two classifying as "likely benign", and one classifying as "VUS". Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000209748	SCV001357613	likely benign	Fabry disease	2018-11-11	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000209748	SCV001423100	likely benign	Fabry disease	2020-01-22	criteria provided, single submitter	curation	The p.Leu3Pro variant in GLA has not been previously reported in individuals with Fabry disease, and has been identified in 0.32% (61/19010) of African chromosomes, including 11 hemizygotes, and 0.0036% (1/28047) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs150547672). This variant has been reported in ClinVar as benign by the Laboratory for Molecular Medicine (Partners Healthcare) and GeneDx, as likely benign by Invitae and Ambry Genetics, and as a VUS by Albrecht-Kossel-Institute (Medical University Rostock) and the Division of Genomic Diagnostics (The Children's Hospital of Philadelphia) (ID:42464). Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4 (Richards 2015).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798076	SCV002042028	benign	Cardiomyopathy	2020-09-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000209748	SCV002054830	likely benign	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Albrecht-Kossel-Institute, Medical University Rostock	RCV000209748	SCV000246017	uncertain significance	Fabry disease	2014-01-01	no assertion criteria provided	research
Albrecht-Kossel-Institute, Medical University Rostock	RCV000209183	SCV000246018	drug response	Migalastat response	2014-01-01	no assertion criteria provided	research
Natera, Inc.	RCV000209748	SCV002081354	benign	Fabry disease	2020-01-06	no assertion criteria provided	clinical testing