ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1105C>T (p.Arg369Cys) (rs772552898)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414057 SCV000491035 pathogenic not provided 2016-09-20 criteria provided, single submitter clinical testing The R369C missense variant in the MUT gene has been reported previously in multiple patients in association with methylmalonic acidemia (MMA) due to methylmalonyl-CoA mutase deficiency (Jung et al. 2005; Ktena et al. 2015; Sakamoto et al. 2007; Merinero et al. 2008; Nizon et al. 2013). R369C is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts R369C is probably damaging to the protein structure/function. Furthermore, a conservative amino acid substitution at the same position (R369H) appears to be a common variant in Japanese patients with MMA and is reported to be associated with 1% of wild-type enzyme activity (Sakamoto et al. 2007). Therefore, we interpret R369C to be a pathogenic variant.
Invitae RCV000203377 SCV000641770 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-10-11 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 369 of the MUT protein (p.Arg369Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs772552898, ExAC 0.01%). This variant has been reported in combination with other MUT variants in multiple individuals affected with methylmalonic acidemia (PMID: 15781199, 16281286, 17075691). ClinVar contains an entry for this variant (Variation ID: 218989). A different missense substitution at this codon (p.Arg369His) has been determined to be pathogenic (PMID: 16281286, 27751223, 25125334, Invitae). This suggests that the arginine residue is critical for MUT protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000203377 SCV000789105 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-01-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000414057 SCV001246220 pathogenic not provided 2019-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193325 SCV001362076 pathogenic Methylmalonic acidemia 2019-02-25 criteria provided, single submitter clinical testing Variant summary: MUT c.1105C>T (p.Arg369Cys) results in a non-conservative amino acid change located in the Methylmalonyl-CoA mutase, alpha chain, catalytic domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 276372 control chromosomes (gnomAD). c.1105C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Forny_2016, Jung_2004, Worgan_2006). These data indicate that the variant is very likely to be associated with disease. Biochemical testing on patients with the variant demonstrated propionate incorporration and MUT activity values that were considerably lower than controls (Forny_2016, Worgan_2006). Four ClinVar submissions from clinical diagnostic laboratories and reputable databases (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneReviews RCV000203377 SCV000258502 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-01-07 no assertion criteria provided literature only

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