ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs779893448
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000664762 SCV000788772 pathogenic Cobalamin C disease 2016-12-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000664762 SCV000919674 pathogenic Cobalamin C disease 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.
Invitae RCV000664762 SCV001402079 pathogenic Cobalamin C disease 2023-09-24 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the MMACHC mRNA. The next in-frame methionine is located at codon 58. This variant is present in population databases (rs779893448, gnomAD 0.003%). Disruption of the initiator codon has been observed in individuals with combined methylmalonic aciduria and homocystinuria (PMID: 16311595, 18164228, 19760748). ClinVar contains an entry for this variant (Variation ID: 203823). For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab RCV000664762 SCV004178125 pathogenic Cobalamin C disease 2023-04-11 criteria provided, single submitter clinical testing
Natera, Inc. RCV001272216 SCV001453985 pathogenic Methylmalonic acidemia with homocystinuria cblC 2020-09-16 no assertion criteria provided clinical testing

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