ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.2080C>T (p.Arg694Trp) (rs777758903)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589534 SCV000696306 pathogenic Methylmalonic acidemia 2017-03-19 criteria provided, single submitter clinical testing Variant summary: The MUT c.2080C>T (p.Arg694Trp) variant located in the AdoCbl-binding domain (via Imtiaz_2014) involves the alteration of a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with the allele frequency of 2/121164 (1/60582), which does not exceed the estimated maximal expected allele frequency of a pathogenic MUT variant for 1/414. Multiple publications have cited the variant in affected homozygous and compound heterozygous individuals. In addition, at-least one database classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000203399 SCV000791014 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-04-24 criteria provided, single submitter clinical testing
Invitae RCV000203399 SCV001222586 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-11-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 694 of the MUT protein (p.Arg694Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs777758903, ExAC 0.006%). This variant has been observed to be homozygous and in combination with another MUT variant in individuals affected with methylmalonic aciduria (PMID: 17957493, 27591164). ClinVar contains an entry for this variant (Variation ID: 218996). This variant has been reported to affect MUT protein function (PMID: 7912889, 25125334). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000203399 SCV000258511 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2016-01-07 no assertion criteria provided literature only

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