ClinVar Miner

Submissions for variant NM_000016.5(ACADM):c.1257C>A (p.Tyr419Ter) (rs753928772)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000579124 SCV000680494 pathogenic not provided 2017-07-13 criteria provided, single submitter clinical testing The Y419X (c.1257 C>A) variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Y419X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The Y419X nonsense variant is predicted to result in a medium chain acyl-CoA dehydrogenase (MCAD) protein that is missing the last 3 amino acids. Furthermore, a different nucleotide substitution at the same position (c.1257 C>G) that also results in Y419X has been reported in association with MCAD deficiency, using alternate nomenclature, and was associated with only 1-2% residual medium chain acyl-CoA dehydrogenase activity compared to wild-type (Koster et al. 2014). In summary, we interpret Y419X (c.1257 C>A) as a pathogenic variant.
Invitae RCV000633659 SCV000754916 uncertain significance Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-09-12 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the ACADM gene (p.Tyr419*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 3 amino acids of the ACADM protein. This variant is present in population databases (rs753928772, ExAC 0.003%). This variant has not been reported in the literature in individuals with ACADM-related disease. ClinVar contains an entry for this variant (Variation ID: 488675). A different variant (c.1257C>G) giving rise to the same protein effect (p.Tyr419*) has been reported in an individual affected with medium-chain acyl-CoA dehydrogenase deficiency (PMID: 24966162). Experimental studies showed that c.1257C>G did not lead to NMD but does impair ACADM enzymatic activity. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Counsyl RCV000633659 SCV000798782 likely pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2018-12-26 no assertion criteria provided clinical testing
Natera Inc RCV000633659 SCV001190641 pathogenic Medium-chain acyl-coenzyme A dehydrogenase deficiency 2019-05-20 no assertion criteria provided clinical testing

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.