ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.4343A>T (p.Asn1448Ile) (rs753484341)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000498742 SCV000590687 uncertain significance not provided 2017-06-22 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The N1448I variant has been published in a patient with HCM; however, this patient also harbored a variant in the NEXN gene and segregation studies were not informative (Waldmuller et al., 2015). This variant is observed in 14/66698 (0.02%) alleles from individuals of European ancestry in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The N1448I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, while a missense variant in the same residue (N1448S) has been reported in the Human Gene Mutation Database in association with HCM (Stenson et al., 2014); the pathogenicity of this variant has not been definitively determined.
Invitae RCV000814172 SCV000954573 uncertain significance Hypertrophic cardiomyopathy 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with isoleucine at codon 1448 of the MYH7 protein (p.Asn1448Ile). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and isoleucine. This variant is present in population databases (rs753484341, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with hypertrophic cardiomyopathy (PMID: 25979592). ClinVar contains an entry for this variant (Variation ID: 432912). 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"). 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.

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.