Submissions for variant NM_000169.3(GLA):c.416A>G (p.Asn139Ser)

gnomAD frequency: 0.00003  dbSNP: rs138886989

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000253073	SCV000319853	likely benign	Cardiovascular phenotype	2020-08-03	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.
GeneDx	RCV000418773	SCV000516566	likely benign	not specified	2017-04-14	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	RCV000526024	SCV000622185	likely benign	Fabry disease	2024-01-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000526024	SCV000913821	likely benign	Fabry disease	2018-07-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000526024	SCV001327854	likely benign	Fabry disease	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000526024	SCV001422639	likely benign	Fabry disease	2020-01-22	criteria provided, single submitter	curation	The p.Asn139Ser variant in GLA has been reported in at least 5 individuals with Fabry disease phenotype (PMID: 23935525, 27431810, 29982630), and has been identified in 0.038% (31/81916) of European (non-Finnish) chromosomes, including 10 hemizygotes, and 0.019% (3/16009) of European (Finnish) chromosomes, including 1 hemizygote, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs138886989). This variant has also been reported in ClinVar as likely benign by GeneDx and Invitae and a VUS by Ambry Genetics (ID: 222253). In vitro functional studies provide some evidence that the p.Asn139Ser variant may not impact protein function (PMID: 29982630, 23935525). However, these types of assays may not accurately represent biological function. 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. One affected individual with this variant has an alternative molecular basis for disease, suggesting that p.Asn139Ser is not causative for this disease (PMID: 27431810). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BP5, BS3_supporting (Richards 2015).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001530102	SCV001744733	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001530102	SCV001931595	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001530102	SCV001951299	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001530102	SCV001966499	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000526024	SCV002081348	likely benign	Fabry disease	2020-03-12	no assertion criteria provided	clinical testing