ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2788G>C (p.Glu930Gln) (rs397516171)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000695329 SCV000199164 likely pathogenic Hypertrophic cardiomyopathy 2013-02-15 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx RCV000158575 SCV000208510 pathogenic not provided 2018-12-26 criteria provided, single submitter clinical testing The E930Q pathogenic variant in the MYH7 gene has been previously published in association with HCM (Girolami et al., 2006; Olivotto et al., 2008; Walsh et al., 2017) and is classified as likely pathogenic by other clinical laboratories in ClinVar (SCV000199164.4; SCV000611213.1, SCV000740378.1; Landrum et al., 2016). This variant has also been found to segregate with HCM in several families who underwent genetic testing at GeneDx. Furthermore, E930Q is not observed in large population cohorts (Lek et al., 2016). Located in the S2 domain of MYH7, E930Q results in a semi-conservative amino acid substitution of a negatively charged glutamic acid with a neutral, polar glutamine. In-silico analyses, including protein predictors and evolutionary conservation, also support a deleterious effect. Moreover, a pathogenic missense variant at this same residue (E930K) and missense variants in nearby residues (D928N, D928G, D928V, D928A, E929K, E931K, E931A, E931G, M932K) have been reported in the Human Gene Mutation Database in association with HCM, further supporting the functional importance of this residue and region of the protein (Stenson et al., 2014).In summary, E930Q in the MYH7 gene is interpreted as a pathogenic variant.
Fulgent Genetics,Fulgent Genetics RCV000515259 SCV000611213 likely pathogenic Familial hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; Myopathy, distal, 1; Scapuloperoneal myopathy, MYH7-related 2017-05-18 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000158575 SCV000740378 likely pathogenic not provided 2017-06-26 criteria provided, single submitter clinical testing
Invitae RCV000695329 SCV000823821 pathogenic Hypertrophic cardiomyopathy 2018-08-10 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 930 of the MYH7 protein (p.Glu930Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with hypertrophic cardiomyopathy in a family (Invitae). This variant has been observed in several individuals affected with hypertrophic cardiomyopathy (PMID: 18533079, 27532257, 27247418, Invitae). ClinVar contains an entry for this variant (Variation ID: 164312). 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). The observation of one or more missense substitutions at this codon (p.Glu930Gln and p.Glu930Lys) in affected individuals suggests that this may be a clinically significant residue (PMID: 19134269, 18533079). For these reasons, this variant has been classified as Pathogenic.

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