ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.851T>C (p.Met284Thr)

dbSNP: rs1928171557
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192393 SCV001360478 pathogenic Fabry disease 2019-08-06 criteria provided, single submitter clinical testing Variant summary: GLA c.851T>C (p.Met284Thr) results in a non-conservative amino acid change in 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 183433 control chromosomes (gnomAD). c.851T>C has been reported in the literature in individuals affected with Fabry Disease (Blanch_1996, Fuller_2015, Benjamin_2017). Affected individuals were found to have <10% normal activity (Benjamin_2017). These data indicate that the variant is likely to be associated with disease. 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 pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001192393 SCV004299635 pathogenic Fabry disease 2023-03-26 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GLA protein function. ClinVar contains an entry for this variant (Variation ID: 928485). This missense change has been observed in individual(s) with Fabry disease (PMID: 8807334, 33204599, 33301762). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 284 of the GLA protein (p.Met284Thr).

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