ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.91C>T (p.Arg31Ter) (rs398123278)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078448 SCV000227075 pathogenic not provided 2013-02-07 criteria provided, single submitter clinical testing
GeneDx RCV000078448 SCV000490626 pathogenic not provided 2015-12-16 criteria provided, single submitter clinical testing The R31X nonsense pathogenic variant in the MUT gene has been reported previously in association with methylmalonic acidemia (MMA) in patients who were homozygous for R31X and who were classified as pathogenic based on propionate incorporation studies in patient fibroblasts (Worgan et al., 2006). The R31X variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
Counsyl RCV000175566 SCV000795253 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-11-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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 RCV000175566 SCV001383404 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-09-27 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. This variant is present in population databases (rs398123278, ExAC 0.01%). This variant has been observed to be homozygous in and in combination with another MUT variant in several individuals affected with methylmalonic acidemia due to methylmalonyl-CoA mutase deficiency (PMID: 16281286, 16435223, 17410422). ClinVar contains an entry for this variant (Variation ID: 92688). Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000175566 SCV000258491 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-12-01 no assertion criteria provided literature only mut(0) enzymatic subtype when homozygous

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