ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.1055C>G (p.Ala352Gly) (rs869312162)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000606004 SCV000731441 uncertain significance not specified 2019-06-28 criteria provided, single submitter clinical testing The p.Ala352Gly variant in GLA has not been previously reported in individuals with clinical features of Fabry disease, but was reported in two individuals with unreported clinical status who were tested for Fabry disease (Lukas 2016). It was also identified in 1/19077 South Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/) and has been reported in ClinVar (Variation ID #217410). In vitro studies suggest that that this variant has a mild reduction in enzymatic activity (Lukas 2016), but these assays may not accurately represent biological function. Computational prediction tools and conservation analysis suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Ala352Gly variant is uncertain.
Color Health, Inc RCV000209785 SCV001351145 uncertain significance Fabry disease 2020-04-15 criteria provided, single submitter clinical testing
Albrecht-Kossel-Institute,Medical University Rostock RCV000209785 SCV000246097 uncertain significance Fabry disease 2014-01-01 no assertion criteria provided research
Albrecht-Kossel-Institute,Medical University Rostock RCV000209219 SCV000246098 drug response Migalastat response 2014-01-01 no assertion criteria provided research
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000209785 SCV000863870 likely pathogenic Fabry disease 2018-05-17 no assertion criteria provided clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000209785 SCV001422926 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided curation The p.Ala352Gly variant in GLA has not been previously reported in individuals with Fabry disease but has been identified in 0.0052% (1/19077) of South Asian chromosomes by the Genome Aggregation Database, including 1 hemizygote (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs869312162). Although this variant has been seen in the general population, its frequency is low enough to be consistent with Fabry disease. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has been reported in ClinVar as Likely Pathogenic by Sonic Healthcare and as a VUS by the Laboratory for Molecular Medicine and the Albrecht-Kossel-Institute (Variation ID:217410). In vitro functional studies provide some evidence that the p.Ala352Gly variant may not impact protein function (PMID: 26415523). 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. In summary, the clinical significance of the p.Ala352Gly variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, BS3_supporting, PM4 (Richards 2015).
Natera, Inc. RCV000209785 SCV001457722 uncertain significance Fabry disease 2020-09-16 no assertion criteria provided clinical testing

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