ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.91C>T (p.Arg31Ter)

gnomAD frequency: 0.00003  dbSNP: rs398123278
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000078448 SCV000227075 pathogenic not provided 2013-02-07 criteria provided, single submitter clinical testing
GeneDx RCV000078448 SCV000490626 pathogenic not provided 2023-09-19 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 34930662, 35361390, 16281286, 25525159, 25959030, 16435223, 17410422, 31998365, 32754920, 33820958, 34668645, 27167370, 31622506, 36186952)
Counsyl RCV000175566 SCV000795253 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-11-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781612 SCV000919784 pathogenic Methylmalonic acidemia 2018-05-07 criteria provided, single submitter clinical testing Variant summary: MUT c.91C>T (p.Arg31X) 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., p.Gly284X and p.Arg467X). The variant allele was found at a frequency of 1.8e-05 in 276662 control chromosomes. This frequency is not higher than expected for a pathogenic variant in MUT causing Methylmalonic Acidemia (1.8e-05 vs 0.0024), allowing no conclusion about variant significance. c.91C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia as both a homozygous and compound heterozygous allele. These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence showing a significant reduction in the propionate incorporation compared to controls (Worgan_2006), suggesting that the methylmalonyl-CoA mutase enzyme is impaired or absent. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000175566 SCV000993428 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-02-07 criteria provided, single submitter research ACMG codes: PVS1, PS3, PM2, PP5
Invitae RCV000078448 SCV001383404 pathogenic not provided 2023-12-20 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg31*) in the MUT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). This variant is present in population databases (rs398123278, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency (PMID: 16281286, 16435223, 17410422). ClinVar contains an entry for this variant (Variation ID: 92688). For these reasons, this variant has been classified as Pathogenic.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein RCV002251962 SCV002523606 pathogenic See cases 2019-05-15 criteria provided, single submitter clinical testing ACMG classification criteria: PVS1, PM2, PP5
Fulgent Genetics, Fulgent Genetics RCV000175566 SCV002792729 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2022-01-17 criteria provided, single submitter clinical testing
GeneReviews RCV000175566 SCV000258491 not provided Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency no assertion provided literature only mut(0) enzymatic subtype when homozygous
Natera, Inc. RCV001826711 SCV002075448 pathogenic Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency 2020-08-04 no assertion criteria provided clinical testing

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