ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.682C>T (p.Arg228Ter) (rs200596762)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186056 SCV000239020 pathogenic not provided 2017-06-22 criteria provided, single submitter clinical testing The R228X nonsense variant has been reported previously in association with methylmalonic acidemia (MMA) (Acquaviva et al., 2005). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R228X 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). Therefore, R228X is interpreted to be pathogenic.
Counsyl RCV000666877 SCV000791244 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-05-15 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000666877 SCV000916152 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-09-27 criteria provided, single submitter clinical testing Across a selection of the available literature, the MUT c.682C>T (p.Arg228Ter) variant has been identified in a homozygous state in at least one proband and in a compound heterozygous state in at least eleven probands with methylmalonic academia (Acquaviva et al. 2005; Chu et al. 2016; Harrington et al. 2016). Control data are unavailable for this variant, which is reported at a frequency of 0.000209 in the Latino population of the Genome Aggregation Database. Based on the evidence and the potential impact of stop-gained variants, the p.Arg228Ter variant is classified as pathogenic for methylmalonic acidemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000666877 SCV000960345 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-10-18 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg228*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs200596762, ExAC 0.003%). This variant has been observed in several individuals affected with MUT-related conditions (PMID: 15643616, 15781192, 27233228). ClinVar contains an entry for this variant (Variation ID: 203855). 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 RCV001192657 SCV001360916 pathogenic Methylmalonic acidemia 2019-05-02 criteria provided, single submitter clinical testing Variant summary: MUT c.682C>T (p.Arg228X) 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. The variant allele was found at a frequency of 6.4e-05 in 250348 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in MUT causing Methylmalonic Acidemia (6.4e-05 vs 0.0024). c.682C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Harrington_2016, Acquaviva_2005). These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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