ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1663G>A (p.Ala555Thr) (rs753564352)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000186050 SCV000239014 likely pathogenic not provided 2013-12-19 criteria provided, single submitter clinical testing The variant p.Ala555Thr (A555T:GCA>ACA): c.1663 G>A in exon 9 of the MUT gene (NM_000255.3) is a missense change that is likely pathogenic. It has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The amino acid change is non-conservative in that a non-polar Alanine residue is replaced by a polar Threonine residue. This change occurs at a highly conserved position in the MUT protein, and missense mutations at nearby positions (A535P, C560Y) have been reported in association with methylmalonic acidemia. Furthermore, multiple in-silico analysis programs predict that A555T is damaging to the MUT protein. Therefore, A555T is a strong candidate for a disease-causing mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in MMA-MET panel(s).
Invitae RCV000210837 SCV001220092 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-10-07 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 555 of the MUT protein (p.Ala555Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs753564352, ExAC 0.03%). This variant has been observed in individual(s) with methylmalonic aciduria (PMID: 26483233, 27233228, Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 203850). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
Institute of Medical Genetics and Genomics,Sir Ganga Ram Hospital RCV000210837 SCV000267122 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2013-05-05 no assertion criteria provided research

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