ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.416A>G (p.Asn139Ser) (rs138886989)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000253073 SCV000319853 uncertain significance Cardiovascular phenotype 2015-07-17 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes)
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 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000526024 SCV000913821 likely benign Fabry disease 2018-07-03 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 Institute Rare Disease Group,Broad Institute RCV000526024 SCV001422639 likely benign Fabry disease 2020-01-22 no assertion criteria provided 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,; 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).

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