ClinVar Miner

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

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000078445 SCV000225762 pathogenic not provided 2015-06-10 criteria provided, single submitter clinical testing
GeneDx RCV000078445 SCV000583146 pathogenic not provided 2021-06-14 criteria provided, single submitter clinical testing Published functional studies demonstrate this variant fails to constitute [14C] propionate incorporation activity (Crane et al., 1992); The majority of missense variants in this gene are considered pathogenic (Stenson et al., 2014 ); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 9285782, 25125334, 24077912, 25087612, 1346616, 16281286, 26790480, 31622506, 27535533)
Counsyl RCV000174456 SCV000788461 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-04-21 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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 RCV000078445 SCV000963062 pathogenic not provided 2020-07-14 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
GeneReviews RCV000174456 SCV000258513 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-01-07 no assertion criteria provided literature only
Natera, Inc. RCV001276629 SCV001463081 pathogenic Methylmalonic aciduria due to complete methylmalonyl-CoA mutase deficiency 2020-09-16 no assertion criteria provided clinical testing

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