ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.850G>T (p.Gly284Ter) (rs761477436)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000669279 SCV000794018 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-09-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781609 SCV000919781 pathogenic Methylmalonic acidemia 2018-04-27 criteria provided, single submitter clinical testing Variant summary: MUT c.850G>T (p.Gly284X) 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.1025C>A (p.Ser342X) and c.1399C>T (p.Arg467X)). The variant was observed with an allele frequency of 1.6e-05 in 246108 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MUT causing Methylmalonic Acidemia (1.6e-05 vs. 0.0024), allowing no conclusion about variant significance. The variant, c.850G>T, has been reported in the literature in individuals affected with Methylmalonic Acidemia (Worgan 2006). These data indicate that the variant may be associated with disease. This publication also reported experimental evidence evaluating an impact on protein function, with the most pronounced variant effect resulting in <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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV000669279 SCV000996212 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-11-15 criteria provided, single submitter clinical testing This nonsense variant found in exon 4 of 13 is predicted to result in loss of normal protein function. This variant has been previously reported as compound heterozygous change in patients with methylmalonic acidemia (PMID: 16281286). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0016% (4/251340) and thus is presumed to be rare. Based on the available evidence, the c.850G>T (p.Gly284Ter) variant is classified as pathogenic.
Invitae RCV000669279 SCV001237143 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-11-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gly284*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs761477436, ExAC 0.03%). This variant has been observed in combination with another MUT variant in individuals affected with methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency (PMID: 16281286). ClinVar contains an entry for this variant (Variation ID: 553762). 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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