ClinVar Miner

Submissions for variant NM_000157.4(GBA):c.1090G>A (p.Gly364Arg) (rs121908305)

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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 RCV000180535 SCV000232997 likely pathogenic not provided 2014-03-07 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197976 SCV001368761 likely pathogenic Gaucher disease, perinatal lethal 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PM2,PP2,PP3.
OMIM RCV000004562 SCV000024736 pathogenic Gaucher disease type II 1990-12-15 no assertion criteria provided literature only
Broad Institute Rare Disease Group, Broad Institute RCV001248922 SCV001422689 likely pathogenic Gaucher disease 2020-01-13 no assertion criteria provided curation The p.Gly364Arg variant in GBA has been reported in at least 3 individuals with Gaucher disease (PMID: 30497978, 25435509, 29685539) and has been Identified in 0.006% (2/34580) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs121908305). 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: 4318) as pathogenic by OMIM and as likely pathogenic by EGL Genetic Diagnostics. In vitro functional studies provide some evidence that the p.Gly364Arg variant may impact protein function (PMID: 30497978). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional likely pathogenic variant, resulting in a different amino acid change at the same position, p.Arg364Trp, has been reported in association with disease in the literature, slightly supporting that a change at this position may not be tolerated (PMID: 17427031, 11259172). In addition, The presence of this variant in in combination with a reported pathogenic variant and in an individual with Gaucher disease increases the likelihood that the p.Gly364Arg variant is pathogenic (VariationID: 4319; PMID: 28727984, 30497978). 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, PM5_supporting (Richards 2015).

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