ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.982C>T (p.Leu328Phe) (rs796052002)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000589433 SCV000696309 pathogenic Methylmalonic acidemia 2017-02-09 criteria provided, single submitter clinical testing Variant summary: The MUT c.982C>T (p.Leu328Phe) variant involves the alteration of a conserved nucleotide and is located in substrate-binding TIM barrel of the protein (Lempp_2007, Dndar_2012). 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 121168 control chromosomes including broad and large population of ExAC. This variant is reported as a pathogenic variant in literature and has been found in several patients with methylmalonic academia in homozygous as well as in compound heterozygous state with other potentially pathogenic variants. Functional studies for this variant are consistent with defective enzymatic activity. One clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Counsyl RCV000666436 SCV000790728 likely pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-04-06 criteria provided, single submitter clinical testing
Invitae RCV000666436 SCV001213820 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-10-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 328 of the MUT protein (p.Leu328Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in several individuals affected with methylmalonic aciduria (PMID: 15643616, 27167370, 17113806). ClinVar contains an entry for this variant (Variation ID: 203844). This variant has been reported to affect MUT protein function (PMID: 25125334). For these reasons, this variant has been classified as Pathogenic.

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