ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.1051A>G (p.Lys351Glu) (rs730880864)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000158781 SCV000208716 likely pathogenic not provided 2017-11-28 criteria provided, single submitter clinical testing The K351E likely pathogenic variant in the MYH7 gene has been previously reported in association with HCM (Mohiddin et al., 2003; Yu et al., 2005; Ingles et al., 2017; Walsh et al., 2017). This variant has also been identified independently of additional cardiogenetic variants in other unrelated patients with HCM referred for genetic testing at GeneDx, and was found to segregate with disease in affected individuals from multiple unrelated families. This variant is not observed in large population cohorts (Lek et al., 2016). The K351E 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. Furthermore, 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.
Ambry Genetics RCV000251987 SCV000319701 likely pathogenic Cardiovascular phenotype 2015-05-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000703741 SCV000832655 uncertain significance Hypertrophic cardiomyopathy 2018-03-05 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 351 of the MYH7 protein (p.Lys351Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (HCM) (PMID: 12820698). This variant has also been reported in several individuals referred for HCM testing (PMID: 27532257, 20800588, 15858117, 25351510). ClinVar contains an entry for this variant (Variation ID: 181335). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 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.

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