ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.3G>A (p.Met1Ile) (rs779893448)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664762 SCV000788772 pathogenic Methylmalonic acidemia with homocystinuria 2016-12-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000664762 SCV000919674 pathogenic Methylmalonic acidemia with homocystinuria 2018-10-29 criteria provided, single submitter clinical testing Variant summary: MMACHC c.3G>A (p.Met1Ile) alters the initiation codon and is predicted to result either in absence of the protein or truncation of the encoded protein due to translation initiation at a downstream codon. Three of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 246258 control chromosomes (gnomAD). c.3G>A has been reported in the literature in multiple individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria)(Lerner-Ellis_2006, Nogueira_2008). 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. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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