ClinVar Miner

Submissions for variant NM_000169.3(GLA):c.559_560del (p.Met187fs)

dbSNP: rs1928287177
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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 RCV001280614 SCV001467833 pathogenic Fabry disease 2020-12-15 criteria provided, single submitter clinical testing Variant summary: GLA c.559_560delAT (p.Met187ValfsX6) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 181428 control chromosomes. c.559_560delAT has been reported in the literature in individuals affected with classic manifestations of Fabry Disease and associated with elevated serum Lyso-Gb3 levels in males with a classic disease presentation (example, Nowak_2019, Nowak_2017, Barbey_2019, Maruyama_2019). At least one publication reports experimental evidence evaluating an impact on protein function in a carrier female. The most pronounced variant effect results in alpha-Gal A enzyme activity within the levels expected for a carrier female and can be extrapolated to <10% of normal activity in classic male patients (Maruyama_2019). 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 RCV001280614 SCV003461841 pathogenic Fabry disease 2022-04-03 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 992230). This premature translational stop signal has been observed in individual(s) with Fabry disease (PMID: 28728877). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Met187Valfs*6) in the GLA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777).

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