ClinVar Miner

Submissions for variant NM_000255.4(MMUT):c.1481T>A (p.Leu494Ter) (rs764173488)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000666288 SCV000790554 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-03-28 criteria provided, single submitter clinical testing
Invitae RCV000666288 SCV000829948 pathogenic Methylmalonic aciduria due to methylmalonyl-CoA mutase deficiency 2017-07-13 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu494*) in the MUT gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs764173488, ExAC 0.01%). This variant has been reported in multiple individuals affected with methylmalonic acidemia (PMID: 23479330, 16490061). 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 RCV001193327 SCV001362078 pathogenic Methylmalonic acidemia 2019-08-05 criteria provided, single submitter clinical testing Variant summary: MUT c.1481T>A (p.Leu494X) 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 (e.g. p.Arg511X, p.Ala732fsX6). The variant allele was found at a frequency of 8e-06 in 250250 control chromosomes. c.1481T>A has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Methylmalonic Acidemia (e.g. Sakamoto_2007, Imataka_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.