ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.153G>A (p.Met51Ile)

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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 RCV001194306 SCV001363731 likely pathogenic Fabry disease 2019-03-14 criteria provided, single submitter clinical testing Variant summary: GLA c.153G>A (p.Met51Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 178708 control chromosomes (ACMG PM2). c.153G>A has been reported in the literature in individuals affected with Fabry Disease. In one Italian family, 8 members carried the variant, including 1 female with normal a-Gal activity, one female with absent activity, and two males with absent activity, one symptomatic and one asymptomatic (Cammarata_2015). Additonally, one neonatal patient has been reported with the variant who had absent a-Gal activity (Spada_2006). Variability in organ involvement and disease severity in patients with this variant has been reported in the literature. These data indicate that the variant is likely to be associated with disease. In vitro studies report the variant to have a-Gal activity ranging from 20-40% in cell lines, however the variant was also shown to negatively impact protein stability (Spada_2006, Tsukimura_2011, Lukas_2013). These in vitro studies have also shown the mutant enzyme activity and stability to be improved by treatment with 1-deoxygalactonojirimycin (DGJ) (ACMG PS3). Additionally, the variant was described as amenable to therapy based on an in vitro assay, according to Galafold (migalastat) insert, which is an FDA approved therapy for Fabry disease. However, the insert also states that the inclusion of a variant in this category does not reflect intepretation of clinical significance in Fabry 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 likely pathogenic.
Invitae RCV001194306 SCV001587276 pathogenic Fabry disease 2020-06-23 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 51 of the GLA protein (p.Met51Ile). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 16773563, 25977923). It has also been observed to segregate with disease in related individuals. This variant has been reported to affect GLA protein function (PMID: 16773563, 23935525, 21517827). For these reasons, this variant has been classified as Pathogenic.

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