ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.2150G>T (p.Gly717Val) (rs121918252)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000174456 SCV000788461 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-04-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000078445 SCV000225762 pathogenic not provided 2015-06-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000174456 SCV000893719 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000078445 SCV000583146 pathogenic not provided 2017-05-24 criteria provided, single submitter clinical testing The G717V variant in the MUT gene has been reported previously in association with methylmalonic acidemia when present in the homozygous state or when in trans with another disease-causing variant, and is a common variant in individuals with African background (Worgan et al., 2006). The G717V variant is observed in 9/10304 (0.08%) alleles from individuals of African background, in the ExAC dataset (Lek et al., 2016). The G717V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. Functional studies demonstrate that the G717V variant fails to constitute [14C] propionate incorporation activity (Crane et al., 1992). We interpret G717V as a pathogenic variant.
GeneReviews RCV000174456 SCV000258513 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-01-07 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000781613 SCV000919785 pathogenic Methylmalonic acidemia 2018-05-25 criteria provided, single submitter clinical testing Variant summary: MUT c.2150G>T (p.Gly717Val) results in a non-conservative amino acid change located in the Cobalamin (vitamin B12)-binding domain and C-terminal of the Methylmalonyl-CoA mutase 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 5.8e-05 in 277004 control chromosomes (gnomAD). The variant, c.2150G>T, has been reported in the literature in multiple individuals affected with Methylmalonic Acidemia as a homozygous and compound heterozygous allele (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 (Worgan_2006). The most pronounced variant effect results in <10% of normal activity. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000174456 SCV000963062 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 717 of the MUT protein (p.Gly717Val). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs121918252, ExAC 0.09%). This variant has been observed to be homozygous or in combination with another MUT variant in several individuals affected with methylmalonic acidemia (PMID: 1346616, 16281286, 27233228). ClinVar contains an entry for this variant (Variation ID: 1881). Experimental studies have shown that this missense change impairs MUT enzymatic activity in vitro (PMID: 1346616, 25125334). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001958 SCV000022116 pathogenic METHYLMALONIC ACIDURIA, mut(-) TYPE 2006-01-01 no assertion criteria provided literature only

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