Submissions for variant NM_000257.4(MYH7):c.2513C>T (p.Pro838Leu)

dbSNP: rs397516153

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000758065	SCV000564430	pathogenic	Restrictive cardiomyopathy	2016-12-15	reviewed by expert panel	curation	The c.2513C>T (p.Pro838Leu) variant in MYH7 has been reported as a de novo occurrence in two individuals with restrictive cardiomyopathy (PS4_Supporting and PS2: PMID:18380764; Partners LMM ClinVar SCV000059450.5). This variant was absent from large population studies (PM2; http://exac.broadinstitute.org). This variant lies in the head region of the protein (aa 181-937) and missense variants in this region are statistically more likely to be disease-associated (PM1; PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for restrictive cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (PMID:29300372): PS2; PM1; PM2; PP3; PS4_ Supporting
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000758065	SCV000059450	pathogenic	Restrictive cardiomyopathy	2013-11-19	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Eurofins Ntd Llc (ga)	RCV000373365	SCV000331348	pathogenic	not provided	2013-03-12	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001221142	SCV001393168	pathogenic	Hypertrophic cardiomyopathy	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 838 of the MYH7 protein (p.Pro838Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (DCM) or restrictive cardiomyopathy (RCM), and left-ventricular non-compaction (LVNC) (PMID: 18380764, 27965028, 28855170, 29300372). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 42910). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt MYH7 protein function with a positive predictive value of 95%. 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). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253340	SCV001429001	pathogenic	Dilated cardiomyopathy 1S	2019-02-08	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000373365	SCV001447987	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000373365	SCV002017665	pathogenic	not provided	2020-10-08	criteria provided, single submitter	clinical testing