ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.661C>T (p.Gln221Ter) (rs797044747)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000178724 SCV000230865 pathogenic not provided 2014-07-11 criteria provided, single submitter clinical testing
Invitae RCV001036876 SCV001200263 pathogenic Fabry disease 2019-12-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln221*) in the GLA gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Fabry disease (PMID: 12175777). ClinVar contains an entry for this variant (Variation ID: 197638). Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001036876 SCV001361654 pathogenic Fabry disease 2019-07-03 criteria provided, single submitter clinical testing Variant summary: GLA c.661C>T (p.Gln221X) 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 183422 control chromosomes. c.661C>T has been reported in the literature in at-least three individuals affected with classic Fabry Disease (Shabbeer_2002 and Tahir_2007). These data indicate that the variant is associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported although the patients identified in the literature were reported to have been tested by enzyme activity for alpha-galactosidase. This variant is listed among the list of mutations "not amenable" to treatment with Galafold (migalastat) in product specifications for this drug. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. However, at-least one submitter in ClinVar classified the variant as pathogenic in 2013. Based on the evidence outlined above, the variant was classified as pathogenic.

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