ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.457C>T (p.Arg153Ter) (rs757325789)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665310 SCV000789407 pathogenic Methylmalonic acidemia with homocystinuria 2017-02-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000665310 SCV000919672 pathogenic Methylmalonic acidemia with homocystinuria 2018-09-24 criteria provided, single submitter clinical testing Variant summary: MMACHC c.457C>T (p.Arg153X) 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. c.481C>T, p.Arg161X; c.547_548delGT, p.Val183fsX5; c.666C>A, p.Tyr222X). The variant allele was found at a frequency of 2e-05 in 245990 control chromosomes (gnomAD and publications). The variant, c.457C>T, has been reported in the literature in multiple individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria)( Lerner-Ellis_2009, Brooks_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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