ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.1102G>C (p.Ala368Pro) (rs144994244)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000418968 SCV000516031 likely benign not specified 2015-03-27 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 RCV000468186 SCV000543772 uncertain significance Fabry disease 2018-10-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with proline at codon 368 of the GLA protein (p.Ala368Pro). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and proline. This variant is present in population databases (rs144994244, ExAC <0.01%) but has not been reported in the literature in individuals with a GLA-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The proline amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
Color RCV000468186 SCV001358841 uncertain significance Fabry disease 2018-11-30 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group,Broad Institute RCV000468186 SCV001422794 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided curation The p.Ala368Pro variant in GLA has not been previously reported in individuals with Fabry disease and has been identified in 0.0043% (4/92620) of European (non-Finnish) chromosomes, including 3 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144994244). 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 also been reported in ClinVar as likely benign by GeneDx and VUS by Invitae (ID: 379288). 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. In summary, the clinical significance of the p.Ala368Pro variant is uncertain. ACMG/AMP Criteria applied: BP4, PM2_supporting (Richards 2015).

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