ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1207C>T (p.Arg403Ter) (rs727504020)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000179277 SCV000789777 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-02-17 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000790701 SCV000231500 pathogenic not provided 2013-12-04 criteria provided, single submitter clinical testing
Invitae RCV000179277 SCV000959453 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-09-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg403*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs727504020, ExAC 0.001%). This variant has been observed in several individuals and families affected with MUT-related conditions (PMID: 12402345, 27167370, 26790480, 27233228, 17113806). ClinVar contains an entry for this variant (Variation ID: 167310). Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000179277 SCV000245636 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2014-12-22 criteria provided, single submitter clinical testing The p.Arg403X variant in MUT has been reported in 1 individual with clinical features of methylmalonic acidemia and no enzyme activity, though a second allele was not identified (Peters 2002). This variant has also been identified in 1/67564 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). Animal models in mice have shown that this variant causes features of the disease (Buck 2012). This nonsense variant leads to a premature termination codon at position 403, which is predicted to lead to a truncated or absent protein. Homozygous or compound heterozygous loss of function of MUT has been shown to cause methylmalonic acidemia. In summary, this variant meets our criteria to be classified as pathogenic for methylmalonic acidemia in an autosomal recessive manner.

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