Submissions for variant NM_000169.3(GLA):c.945C>T (p.Asp315=)

gnomAD frequency: 0.00009  dbSNP: rs151208856

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035315	SCV000058963	likely benign	not specified	2013-06-17	criteria provided, single submitter	clinical testing	p.Asp315Asp in exon 6 of GLA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 0.02% (15/90617) of European chromosomes, including 5 hemizygotes, by the Genome Aggregation Databas e (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs151208856).
GeneDx	RCV000035315	SCV000207804	benign	not specified	2012-12-11	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.
Invitae	RCV000557645	SCV000622196	likely benign	Fabry disease	2023-12-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000585389	SCV000693354	uncertain significance	not provided	2017-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000035315	SCV000919434	likely benign	not specified	2017-11-16	criteria provided, single submitter	clinical testing	Variant summary: The GLA c.945C>T (p.Asp315Asp) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing (1 tool predicts a decreased affinity for a cryptic donor splice site). ESE finder predicts that this variant may affect a binding site for SF2/ASF. However, these predictions have yet to be confirmed by functional studies. This variant was found in 19/200260 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000166 (15/90617) with 5 hemizygous occurrences, that exceeds the disease prevalence (1/50000), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases; nor evaluated for functional impact by in vivo/vitro studies. In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, based mainly on the in silico predictions and the observed hemizygous occurrences this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000557645	SCV001350818	likely benign	Fabry disease	2018-10-30	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000557645	SCV001422921	likely benign	Fabry disease	2020-01-22	criteria provided, single submitter	curation	The c.945C>T variant in GLA has not been previously reported in individuals with Fabry disease, but has been identified in 0.017% (16/92661) of European (non-Finnish) chromosomes, including 6 hemizygotes, and 0.014% (4/28052) of Latino chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org/; dbSNP rs151208856). This variant has been seen in the general population at a greater frequency than expected for Fabry disease and is consistent with a benign role. This variant has been reported in ClinVar as likely benign by the Laboratoy for Molecular Medicine, Invitae, and the University Medical Center Groningen, as benign by GeneDx, and as a VUS by Praxis fuer Humangenetik Tuebingen (Variation ID: 42465). 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_supporting, BP4, BP7 (Richards 2015).
Genome-Nilou Lab	RCV000557645	SCV002054797	likely benign	Fabry disease	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002371820	SCV002688319	benign	Cardiovascular phenotype	2021-01-19	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
PreventionGenetics, part of Exact Sciences	RCV003974871	SCV004786664	likely benign	GLA-related condition	2020-09-17	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000557645	SCV000734723	likely benign	Fabry disease		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035315	SCV001924891	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000585389	SCV001931561	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000585389	SCV001958879	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000585389	SCV001972731	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000557645	SCV002081334	likely benign	Fabry disease	2021-07-25	no assertion criteria provided	clinical testing