ClinVar Miner

Submissions for variant NM_000257.4(MYH7):c.2594A>G (p.Lys865Arg)

gnomAD frequency: 0.00001  dbSNP: rs758891557
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000628947 SCV000749855 pathogenic Hypertrophic cardiomyopathy 2022-07-19 criteria provided, single submitter clinical testing This variant disrupts the p.Lys865 amino acid residue in MYH7. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21310275, 24793961, 27532257). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 524996). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 16858239, 27247418). This variant is present in population databases (rs758891557, gnomAD 0.0009%). This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 865 of the MYH7 protein (p.Lys865Arg).
MGZ Medical Genetics Center RCV002289917 SCV002580579 likely pathogenic Hypertrophic cardiomyopathy 1 2022-02-10 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV003144402 SCV003834074 likely pathogenic not provided 2021-11-22 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002764 SCV004827281 likely pathogenic Primary dilated cardiomyopathy 2023-11-08 criteria provided, single submitter clinical testing The c.2594A>G (p.Lys865Arg) variant in the MYH7 gene has been identified in at least four individuals with Hypertrophic Cardiomyopathy (HCM) (PMID:16858239, 18533079, 21835320, 25524337, 32228044) and two individuals with dilated cardiomyopathy (PMID: 32880476, 34194005). This variant lies in the established functional domain (amino acids 181-937) of the MYH7 protein without benign variations, and missense variants in this region are statistically more likely to be disease-associated (PMID:27532257). In-silico computational prediction tools suggest that this variant may have deleterious effect on the protein function (REVEL score: 0.746). This variant is found to be rare (1/251464; 0.000397%) in the general population database (gnomAD) and interpreted as likely pathogenic/pathogenic by multiple submitters in the ClinVar database (ClinVar ID: 524996). Other missense changes affecting the same amino acid, c.2593A>G (p.Lys865Glu) and c.2594A>T (p.Lys865Met), have been reported in individuals with hypertrophic cardiomyopathy (PMID:27247418, 32894683, 24793961) and interpreted as likely pathogenic by several ClinVar submitters in the ClinVar database (ClinVar ID:181195, 454358), including the ClinGen Cardiomyopathy Variant Curation Expert Panel (ClinVar ID:181195). Therefore, the c.2594A>G (p.Lys865Arg) variant in the MYH7 gene is classified as likely pathogenic.

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