ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1052G>C (p.Trp351Ser) (rs1553217294)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587644 SCV000697573 likely pathogenic Gaucher disease 2016-08-29 criteria provided, single submitter clinical testing Variant summary: The GBA c.1052G>C (p.Trp351Ser) variant involves the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. This variant is located in the catalytic domain and/or the TIM-barrel domain (InterPro). This variant was absent in 121240 control chromosomes, but has been reported by two studies in the literature (Stirnemann_2012, Malini_2013). In a patient reported by Malini_2013, it was found in compound heterozygous state with another likely pathogenic variant, p.Leu483Pro, in a patient with type 1 Gaucher disease. By an in vitro functional study, this variant was found to abrogate the enzymatic activity (Malini_2013). Additionally, one reputable database (HGMD) has classified it as a disease-causing mutation. Taken together, this variant is classified as Likely Pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV000587644 SCV001422533 likely pathogenic Gaucher disease 2020-01-15 no assertion criteria provided curation The p.Trp351Ser variant in GBA has been reported in at least 2 individuals with Gaucher disease (PMID: 24022302, 28034821, 25326392) and was absent from large population studies. This variant has also been reported in ClinVar (VariationID: 49608) as likely pathogenic by Integrated Genetics. In vitro functional studies demonstrating that the variant results in null beta-glucosidase activity provide some evidence that the p.Trp351Ser variant may impact protein function (PMID: 24022302). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with a reported pathogenic variant and in at least one individual with Gaucher disease slightly increases the likelihood that the p.Trp351Ser variant is pathogenic (VariationID: 4288; PMID: 28034821, 24022302). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM2, PS3_moderate, PM3_supporting, PP3 (Richards 2015).

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