ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1531C>T (p.Arg511Ter) (rs761525156)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000672079 SCV000797141 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781614 SCV000919786 pathogenic Methylmalonic acidemia 2018-07-19 criteria provided, single submitter clinical testing Variant summary: MUT c.1531C>T (p.Arg511X) 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 not been classified by our laboratory, however, they have been classified as pathogenic in ClinVar (eg. c.1975C>T/p.Gln659Ter, c.2078delG/p.Gly693Aspfs). The variant allele was found at a frequency of 8.3e-06 in 119944 control chromosomes. c.1531C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia, including as a homozygous allele. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating MUT activity, which showed activity levels <10% of normal activity. 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 RCV000672079 SCV000935646 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-12-04 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg511*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs761525156, ExAC 0.006%). This variant has been observed to be homozygous or in combination with another MUT variant in several individuals affected with methylmalonic aciduria (PMID: 15643616, 27591164, 26454439, 27167370, 16281286). ClinVar contains an entry for this variant (Variation ID: 556124). Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). For these reasons, this variant has been classified as Pathogenic.

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