ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1231G>A (p.Val411Ile) (rs730880868)

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
GeneDx RCV000158790 SCV000208725 uncertain significance not provided 2018-11-28 criteria provided, single submitter clinical testing TThe V411I variant of uncertain significance in the MYH7 gene has been published multiple times in association with HCM, yet familial segregation data was either unavailable or not provided in these studies (Erdmann et al., 2003; Woo et al., 2003; Yu et al., 2005; Millat et al., 2010; Teirlinck et al., 2012; Mook et al., 2013; Viswanathan et al., 2017). Similarly, although this variant has been identified independently in several unrelated individuals referred for HCM genetic testing at GeneDx, observation in these individuals, for whom segregation data is lacking, is not sufficient to determine the absolute pathogenicity of this variant. V411I was observed in 2/34,420 (0.006%) alleles from individuals of Latino ancestry, and globally in 6/277,216 (0.002%) alleles from individuals of various ancestral backgrounds in large population cohorts (Lek et al., 2016). The V411I variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Moreover, in silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Finally, while multiple missense variants in nearby residues (V406M, G407C, G407V, N408K, Y410D, T412N) have been reported in the Human Gene Mutation Database in association with cardiomyopathy (Stenson et al., 2014), the pathogenicity of the majority of these variants has not been definitively determined.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Ambry Genetics RCV000619862 SCV000740068 likely pathogenic Cardiovascular phenotype 2016-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000697577 SCV000826197 uncertain significance Hypertrophic cardiomyopathy 2018-06-28 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 411 of the MYH7 protein (p.Val411Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs730880868, ExAC 0.009%). This variant has been observed in individuals affected with hypertrophic cardiomyopathy (PMID: 12974739, 27532257, 15858117, 20800588, 22429680, 12975413, 29121657, 23785128).  ClinVar contains an entry for this variant (Variation ID: 181339). This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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.