ClinVar Miner

Submissions for variant NM_000169.2(GLA):c.679C>T (p.Arg227Ter) (rs104894841)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000157897 SCV000110133 pathogenic not provided 2018-05-08 criteria provided, single submitter clinical testing
GeneDx RCV000157897 SCV000207828 pathogenic not provided 2017-10-24 criteria provided, single submitter clinical testing The R227X nonsense mutation in the GLA gene has been reported previously in association with Fabry disease (Davies et al., 1993; Shimotori et al., 2007). This mutation is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Approximately 60-70% of females with a single GLA mutation have some disease manifestations, and 10% of these individuals present with a disease severity that is similar to that of affected males (Bennett et al., 2002).The variant is found in GLA panel(s).
Invitae RCV000011479 SCV000965451 pathogenic Fabry disease 2019-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg227*) 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 individuals affected with Fabry disease including one female who is also affected with hypertrophic cardiomyopathy (PMID: 26047621, 25439755, 8395937, 18205205). ClinVar contains an entry for this variant (Variation ID: 10733). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 RCV000011479 SCV001363733 pathogenic Fabry disease 2020-08-21 criteria provided, single submitter clinical testing Variant summary: GLA c.679C>T (p.Arg227X) 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 183590 control chromosomes (gnomAD and publication data). c.679C>T has been reported in the literature in multiple individuals affected with Fabry Disease (Ashley_2001, Davies_1993, Germain_2002, Gomez_2012, Nakano_2013, Giugliani_2013). These data indicate that the variant is very likely to be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000011479 SCV000031711 pathogenic Fabry disease 1993-12-01 no assertion criteria provided literature only
Blueprint Genetics RCV000011479 SCV000188767 pathogenic Fabry disease 2014-01-30 no assertion criteria provided clinical testing

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