ClinVar Miner

Submissions for variant NM_032601.4(MCEE):c.139C>T (p.Arg47Ter) (rs111033538)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000598126 SCV000700785 pathogenic not provided 2017-01-27 criteria provided, single submitter clinical testing
GeneDx RCV000598126 SCV000748189 pathogenic not provided 2018-02-16 criteria provided, single submitter clinical testing The R47X variant has been reported previously in the homozygous state in individuals with mild and moderate methylmalonic aciduria (Dobson et al. 2006; Bikker et al., 2006). In vitro studies of cultured fibroblasts from an affected individual showed decreased 14 C-propionate incorporation and normal (2R)-methylmalonyl-CoA mutase activity. Biochemical analysis of the affected individual's heterozygous parents showed normal urinary excretion of methylmalonic acid (Bikker et al., 2006). The R47X variant is observed in 59/126,544 (0.047%) alleles from individuals of non-Finnish European background, and 69/276,966 global alleles (0.025%) with no homozygous control individuals reported, in large population cohorts (Lek et al., 2016). The R47X is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret R47X as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000002434 SCV000894290 pathogenic Methylmalonyl-CoA epimerase deficiency 2018-10-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000002434 SCV000915922 pathogenic Methylmalonyl-CoA epimerase deficiency 2018-02-12 criteria provided, single submitter clinical testing The MCEE c.139C>T (p.Arg47Ter) variant is a stop-gained variant that is predicted to result in premature termination of the protein. It has been reported in eight patients with methylmalonic acidemia (Bikker et al. 2006; Dobson et al. 2006; Gradinger et al. 2007; Mazzuca et al. 2015; Waters et al. 2016; Abily-Donval et al. 2017). Within this group, which included two sibling pairs, seven individuals were homozygous; the remaining patient was compound heterozygous for p.Arg47Ter and an intron variant that induced aberrant splicing. The phenotypic presentation of these patients was variable, ranging from the absence of clinical symptoms to language, motor, and neurological impairment. In two unrelated patients with a more severe phenotype, the methylmalonyl-CoA epimerase deficiency was combined with sepiapterin reductase deficiency. In at least one homozygous patient, inheritance of the variant from healthy carrier parents was demonstrated. The p.Arg47Ter variant was absent from 197 control individuals and is reported at a frequency of 0.000698 in the European American population of the Exome Sequencing Project. Fibroblasts from homozygous patients were complemented by mut, cblA, and cblB fibroblasts and infection with wild type MCEE cDNA corrected the biochemical phenotype, consistent with decreased [14C]propionate incorporation due to reduced epimerase function (Gradinger et al. 2007). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg47Ter 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.
OMIM RCV000002434 SCV000022592 pathogenic Methylmalonyl-CoA epimerase deficiency 2006-08-01 no assertion criteria provided literature only
GeneReviews RCV000002434 SCV000258535 pathogenic Methylmalonyl-CoA epimerase deficiency 2016-01-07 no assertion criteria provided literature only

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