ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.119C>T (p.Pro40Leu) (rs398123199)

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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 RCV000781427 SCV000919445 likely pathogenic Fabry disease 2019-06-19 criteria provided, single submitter clinical testing Variant summary: GLA c.119C>T (p.Pro40Leu) 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 178720 control chromosomes. c.119C>T has been reported in the literature in individuals affected with Fabry Disease (Lenders_2016, Morrone_2003, Ashton-Prolla_2000). In one report, the patient had <10% WT alpha-galactosidase activity in leucocytes, further supporting the pathogenic outcome of this variant (Morrone_2003). Other variants at the same codon position have been reported as pathogenic or likely pathogenic in ClinVar and HGMD, suggesting this codon is a potential hotspot for mutation (p.Pro40Arg, p.Pro40Ser). 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 RCV000781427 SCV001587277 pathogenic Fabry disease 2020-03-18 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 40 of the GLA protein (p.Pro40Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 12920095, 10916280, 27356758, Invitae). ClinVar contains an entry for this variant (Variation ID: 633248). This variant has been reported to affect GLA protein function (PMID: 27657681). This variant disrupts the p.Pro40 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 2152885, 26415523, 20367968, 19320660), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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