ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1399C>T (p.Arg467Ter) (rs774159791)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000587544 SCV000696305 pathogenic Methylmalonic acidemia 2016-04-11 criteria provided, single submitter clinical testing Variant summary: The MUT c.1399C>T variant results into nonsense mutation in exon 7 predicted to cause a loss of protein function due to production of a truncated protein or nonsense-mediated mRNA decay. It was exclusively observed in the Non-Finnish European sub-cohort of the ExAC project at an allele frequency of 0.0015%, which does not exceed the maximal expected allele frequency of a disease-causing MUT allele (0.24%). In the literature, the variant was observed in several patients with methylmalonic aciduria in compound heterozygosity with other truncating as well as missense variants, consistent with a disease-causing nature. Two reputable databases as well as one clinical lab has classified this variant as pathogenic. Considering all evidence, the variant has been classified as a Disease Variant/Pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV000664980 SCV000916151 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-10-05 criteria provided, single submitter clinical testing The MUT c.1399C>T (p.Arg467Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. This variant has been described in five studies in eight probands with classic methylmalonic acidemia (MMA), with one in a homozygous state and seven in a compound heterozygous state (Peters et al. 2002; Acquaviva et al. 2005; Worgan et al. 2006; Dündar et al. 2012; Liu et al. 2012). The p.Arg467Ter variant was absent from 48 anonymous controls and is reported at a frequency of 0.001320 in the Ashkenazi Jewish population of the Genome Aggregation Database. Functional studies showed that six of the patients (one homozygote and five compound heterozygotes) carrying the p.Arg467Ter variant demonstrated zero enzyme activity ('mut0' phenotype) (Acquaviva et al. 2005). Based on the potential impact of truncating variants and presence in affected individuals, the p.Arg467Ter 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.
Counsyl RCV000664980 SCV000789026 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-01-03 no assertion criteria provided clinical testing

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