ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1420C>T (p.Arg474Ter) (rs887126161)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000670581 SCV000795450 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-11-08 criteria provided, single submitter clinical testing
Invitae RCV000670581 SCV000963824 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2019-08-29 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg474*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous or in combination with another MUT variant in individuals affected with methylmalonic aciduria (PMID: 15643616, 16281286). ClinVar contains an entry for this variant (Variation ID: 554873). Loss-of-function variants in MUT are known to be pathogenic (PMID: 15781192). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001193332 SCV001362083 pathogenic Methylmalonic acidemia 2019-12-20 criteria provided, single submitter clinical testing Variant summary: MUT c.1420C>T (p.Arg474X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251244 control chromosomes (gnomAD). c.1420C>T has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Methylmalonic Acidemia (e.g. Acquaviva_2015, Forny_2016, Worgan_2006). These data indicate that the variant is very likely to be associated with disease. Biochemical studies report low incorporation of propionate and low MUT enzyme activity for cells with the variant and assign mut0 class (Forny_2016, Worgan_2006). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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