ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.572C>A (p.Ala191Glu) (rs760782399)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186054 SCV000239018 pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing The p.Ala191Glu [A191E:GCA>GAA: c.572 C>A in exon 3 of the MUT gene (NM_000255.3)] missense variant in the MUT gene has been reported previously in association with methylmalonic acidemia (MMA) (Worgan et al., 2006).
Invitae RCV000203406 SCV000641781 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2018-11-05 criteria provided, single submitter clinical testing This sequence change replaces alanine with glutamic acid at codon 191 of the MUT protein (p.Ala191Glu). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and glutamic acid. This variant is present in population databases (rs760782399, ExAC 0.009%). This variant is a well known cause of methylmalonic acidemia and it has been reported in the literature in multiple affected individuals (PMID: 16281286, 24059531, 17957493, 15643616, 17113806, 20549364). ClinVar contains an entry for this variant (Variation ID: 203854). Experimental studies have shown that this missense change causes folding defects and impairs catalytic function of the encoded protein (PMID: 25125334).  In addition, assays in affected individuals' fibroblasts have shown reduced enzymatic activity (PMID: 17113806, 16281286). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000585983 SCV000696307 pathogenic Methylmalonic acidemia 2017-03-20 criteria provided, single submitter clinical testing Variant summary: The MUT c.572C>A (p.Ala191Glu) variant located in the alpha chain, catalytic domain (via InterPro) involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools (SNPs&GO not captured due to low reliability index). This variant was found in 6/121172 control chromosomes from ExAC at a heterozygous allele frequency of 0.0000495, which does not exceed the estimated maximal expected allele frequency of a pathogenic MUT variant (0.0024152). This variant is a frequent disease-causing mutation found in several patients in homozygous as well as compound heterozygous state with other likely pathogenic/pathogenic variants with consistent biochemical phenotype (Adjalla_1998, Worgan_2006, de Keyzer_2009, Nizon_2013, Manoli_2016). In addition, one in vitro functional study showed that this variant leads to impairment of folding as well catalytic activity of protein (Forny_2014). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000186054 SCV000885744 pathogenic not provided 2018-05-05 criteria provided, single submitter clinical testing The p.Ala191Glu (rs760782399) is one a commonly associated variants with Methylmalonic aciduria (Adjalla 1998, Worgan 2006, and GeneReviews pubmed ID 20301409). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.004 percent (identified on 10 out of 277,004 chromosomes) and has been reported to the ClinVar database with a pathogenic classification (variation ID: 203854). Expression of the variant MUT protein in bacteria results in poor solubility (Forny 2014) consistent with high conservation of the alanine at position 191 and damaging effects by computational predictor algorithms (SIFT: damaging, PolyPhen-2: probably damaging). Based on these observations the p.Ala191Glu variant is considered to be likely pathogenic.
GeneReviews RCV000203406 SCV000258497 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-01-07 no assertion criteria provided literature only
Counsyl RCV000203406 SCV000794657 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-10-10 no assertion criteria provided clinical testing

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