ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.454C>T (p.Arg152Ter) (rs780068818)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000489927 SCV000576917 pathogenic not provided 2017-04-14 criteria provided, single submitter clinical testing The R152X nonsense variant in the MUT gene has been reported previously in association with methylmalonic acidemia. (Martínez et al., 2005; Dündar et al., 2012; Sawangareetrakul et al., 2015). The R152X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret R152X to be a pathogenic variant.
Invitae RCV000667884 SCV000833732 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg152*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs780068818, ExAC 0.01%). This variant has been reported in combination with other MUT variants in individuals affected with methylmalonic acidemia (PMID: 16281286). ClinVar contains an entry for this variant (Variation ID: 426467). Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001192658 SCV001360917 pathogenic Methylmalonic acidemia 2019-07-19 criteria provided, single submitter clinical testing Variant summary: MUT c.454C>T (p.Arg152X) 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. The variant allele was found at a frequency of 2.4e-05 in 245204 control chromosomes (gnomAD). The variant, c.454C>T, has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Martinez_2005, Wogan_2006, Liu_2012). These data indicate that the variant is very likely to be associated with disease. One publication, Liu_2012, reports that variant effect results in <10% of normal activity. Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000667884 SCV000792396 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-06-27 no assertion criteria provided clinical testing
Natera, Inc. RCV001271720 SCV001453068 pathogenic Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency 2020-09-16 no assertion criteria provided clinical testing

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