ClinVar Miner

Submissions for variant NM_015506.3(MMACHC):c.545_546GT[1] (p.Val183fs) (rs1305170860)

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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 RCV000790832 SCV000331393 pathogenic not provided 2013-05-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000266579 SCV000919667 pathogenic Methylmalonic acidemia with homocystinuria 2018-04-11 criteria provided, single submitter clinical testing Variant summary: MMACHC c.547_548delGT (p.Val183ThrfsX5) 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 (e.g. c.609G>A (p.Trp203X), c.615C>G (p.Tyr205X), c.666C>A (p.Tyr222X)). The variant was absent in 120978 control chromosomes. c.547_548delGT has been reported in the literature in multiple individuals affected with Cobalamin C Disease (Methylmalonic Aciduria with Homocystinuria), both as a homozygous and compound heterozygous allele (Lerner-Ellis 2006, Weisfeld-Adams 2013, Lerner-Ellis 2009). These data indicate that the variant is very likely to be associated with disease. One of these studies also reported that patients fibroblasts had decreased cobalamin coenzyme synthesis and decreased signal incorporation from radiolabeled propionate and 5-methyltetrahydrofolate (Lerner-Ellis 2006). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000266579 SCV000956601 pathogenic Methylmalonic acidemia with homocystinuria 2018-09-10 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the MMACHC gene (p.Val183Thrfs*5). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 100 amino acids of the MMACHC protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another MMACHC variant in individuals affected with methylmalonic aciduria and homocystinuria (PMID: 16311595, 19370762, 23954310). ClinVar contains an entry for this variant (Variation ID: 95704). A different truncation (p.Trp203*) that lies downstream of this variant has been determined to be pathogenic (PMID: PMID: 16311595, 23954310, 25772322). This suggests that deletion of this region of the MMACHC protein is causative of disease. For these reasons, this variant has been classified as Pathogenic.

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