ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.1067G>A (p.Arg356Gln) (rs869312163)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000536023 SCV000622180 likely pathogenic Fabry disease 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 356 of the GLA protein (p.Arg356Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with GLA-related conditions (PMID: 19621417, 27238910, 28615118, 31956509). ClinVar contains an entry for this variant (Variation ID: 222135). This variant has been reported to have conflicting or insufficient data to determine the effect on GLA protein function (PMID: 19621417, 23935525, 28615118). This variant disrupts the p.Arg356 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21598360, 17555407, 25611685, 2539398, 17532296, 24582695). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000734623 SCV000862779 uncertain significance not provided 2018-08-09 criteria provided, single submitter clinical testing
Color Health, Inc RCV000536023 SCV001357986 uncertain significance Fabry disease 2019-11-25 criteria provided, single submitter clinical testing
Broad Institute Rare Disease Group, Broad Institute RCV000536023 SCV001423101 uncertain significance Fabry disease 2020-01-22 no assertion criteria provided curation The p.Arg356Gln variant in GLA has been reported in multiple individuals with Fabry disease (PMID: 19621417, 27238910, 23826564, 28615118), and has been identified in 0.0076% (1/13161) African chromosomes, including one hemizygote, and 0.0012% (1/81755) European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs869312163). 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 pathogenic by Invitae and as a VUS by EGL Genetic Diagnostics (Variation ID:222135). In vitro functional studies provide some evidence that the p.Arg356Gln variant may slightly impact protein function through decreased GLA enzyme activity (PMID: 28615118, 27238910, 19621417). 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, causing a different amino acid change at the same position, (p.Arg356Trp), has been reported in association with disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 23935525, 22773828, 17555407, 17532296, 20031620, 23537685, 2539398, 21598360, 22551898, 26415523;Variation ID:217411,10713). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PM5_supporting, PS3_supporting (Richards 2015).

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