ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.266T>G (p.Leu89Arg)

dbSNP: rs1569304886
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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 RCV000781422 SCV000919440 likely pathogenic Fabry disease 2018-05-06 criteria provided, single submitter clinical testing Variant summary: GLA c.266T>G (p.Leu89Arg) 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 87749 control chromosomes. c.266T>G has been reported in the literature in individuals affected with Fabry Disease. Multiple publications found that the variant causes <10% of normal enzyme activity (Wu_2011; Benjamin_2009). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000781422 SCV002305933 likely pathogenic Fabry disease 2022-08-23 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 89 of the GLA protein (p.Leu89Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Fabry disease (PMID: 7531540, 19387866). ClinVar contains an entry for this variant (Variation ID: 633245). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects GLA function (PMID: 21598360). This variant disrupts the p.Leu89 amino acid residue in GLA. Other variant(s) that disrupt this residue have been observed in individuals with GLA-related conditions (PMID: 9100224; Invitae), which suggests that this may be a clinically significant amino acid residue. 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.

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