ClinVar Miner

Submissions for variant NM_000255.3(MMUT):c.322C>T (rs121918257)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000001964 SCV000595872 pathogenic METHYLMALONIC ACIDURIA, mut(0) TYPE 2016-04-06 criteria provided, single submitter clinical testing
Invitae RCV000203340 SCV000641779 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 108 of the MUT protein (p.Arg108Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs121918257, ExAC 0.09%). This variant has been reported in the literature in multiple individuals affected with methylmalonic acidemia as homozygous or in combination with other MUT variants (PMID: 16281286, 17075691, 24059531, 23045948, 2661559, 22614770, 24464670, 27578510). ClinVar contains an entry for this variant (Variation ID: 1887, 216966). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg108His) has been determined to be pathogenic (PMID: 16281286, 25750861, 23430940, 17113806, 22614770). 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.
Integrated Genetics/Laboratory Corporation of America RCV001192656 SCV001360915 pathogenic Methylmalonic acidemia 2019-01-14 criteria provided, single submitter clinical testing Variant summary: MUT c.322C>T (p.Arg108Cys) 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 0.00011 in 246146 control chromosomes. c.322C>T has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia (Worgan_2006, Harrington_2016). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity as measured by decreased incorporation of label from carbon-14 labeled propionate into cellular macromolecules (Worgan_2006). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000001964 SCV000022122 pathogenic METHYLMALONIC ACIDURIA, mut(0) TYPE 2006-01-01 no assertion criteria provided literature only
GeneReviews RCV000203340 SCV000258495 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-12-01 no assertion criteria provided literature only mut(0) enzymatic subtype when homozygous

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