ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1276G>A (p.Gly426Arg)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286063 SCV001472583 likely pathogenic none provided 2020-01-09 criteria provided, single submitter clinical testing The MMUT c.1276G>A; p.Gly426Arg variant (rs769922244) is reported in the literature in at least one individual affected with methylmalonic aciduria (Worgan 2006). This variant is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 426 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses demonstrate destabilization of the protein and reduced activity (Forny 2014, Worgan 2006). Additionally, another variant at this codon (c.1277G>A; p.Gly426Glu) has been reported in the homozygous state in an individual with methylmalonic aciduria (Forny 2016). Based on available information, this variant is considered to be likely pathogenic. References: Forny P et al. Functional characterization and categorization of missense mutations that cause methylmalonyl-CoA mutase (MUT) deficiency. Hum Mutat. 2014 Dec;35(12):1449-58. Forny P et al. Molecular Genetic Characterization of 151 Mut-Type Methylmalonic Aciduria Patients and Identification of 41 Novel Mutations in MUT. Hum Mutat. 2016 Aug;37(8):745-54. Worgan LC et al. Spectrum of mutations in mut methylmalonic acidemia and identification of a common Hispanic mutation and haplotype. Hum Mutat. 2006 Jan;27(1):31-43.

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