ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1060G>C (p.Asp354His) (rs398123526)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000180536 SCV000232998 pathogenic not provided 2013-08-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781410 SCV000919417 uncertain significance not specified 2018-10-15 criteria provided, single submitter clinical testing Variant summary: GBA c.1060G>C (p.Asp354His) results in a non-conservative amino acid change located in the Glycosyl hydrolase family 30, TIM-barrel domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 121322 control chromosomes. c.1060G>C has been reported in the literature in an individual affected with Gaucher Disease (Walley_1995). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as VUS - possibly pathogenic.
Broad Institute Rare Disease Group, Broad Institute RCV001248921 SCV001422686 uncertain significance Gaucher disease 2020-01-15 no assertion criteria provided curation The p.Asp354His variant in GBA has been reported in one Ashkenazi Jewish individual with Gaucher disease (PMID: 8547070) and has been identified in 0.003% (3/113764) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs398123526). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 93444) as pathogenic by EGL Genetic Diagnostics. 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 an individual with Gaucher disease increases the likelihood that the p.Asp354His variant is pathogenic (VariationID: 4290; PMID: 8547070). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2, PP3, PM3_supporting (Richards 2015).
Natera, Inc. RCV001248921 SCV001461742 uncertain significance Gaucher disease 2020-09-16 no assertion criteria provided clinical testing

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