ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.658C>T (p.Arg220Ter) (rs727503949)

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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 RCV000723942 SCV000202800 pathogenic not provided 2017-08-23 criteria provided, single submitter clinical testing
Invitae RCV000153320 SCV000622191 pathogenic Fabry disease 2019-08-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg220*) 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 reported in multiple individuals affected with Fabry disease (PMID: 7951217, 23980562, 15702404). ClinVar contains an entry for this variant (Variation ID: 167140). Loss-of-function variants in GLA are known to be pathogenic (PMID: 10666480, 12175777, 18698230, 17532296). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000153320 SCV001361590 pathogenic Fabry disease 2019-03-13 criteria provided, single submitter clinical testing Variant summary: GLA c.658C>T (p.Arg220X) 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 (eg. p.Arg227X, p.Lys240fsX9, p.Ile242fsX8). The variant was absent in 178788 control chromosomes. c.658C>T has been reported in the literature in multiple individuals affected with Fabry Disease (Germain_2002, Meaney_1994, Mills_2005, Ries_2005, Schafer_2005, Shin_2007) and is reported to be non-enhanceable by 1-deoxygalactonojirimycin (DGJ) (Shin_2007). These data indicate that the variant is very likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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