ClinVar Miner

Submissions for variant NM_000257.3(MYH7):c.2761G>A (p.Glu921Lys) (rs730880759)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158572 SCV000208507 uncertain significance not provided 2017-02-03 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH7 gene. The E921K variant has previously been reported in association with HCM (Van Driest et al., 2004; Santos et al., 2012). In addition, this variant has also been observed in other unrelated individuals referred for HCM genetic testing at GeneDx. So far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. This variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The E921K 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, to our knowledge no studies have been performed to determine the functional effect of the E921K variant.
Invitae RCV000549326 SCV000623683 likely pathogenic Hypertrophic cardiomyopathy 2017-08-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 921 of the MYH7 protein (p.Glu921Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in two individuals with hypertrophic cardiomyopathy (PMID: 15358028, 22429680). ClinVar contains an entry for this variant (Variation ID: 181205). 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). 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). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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