Submissions for variant NM_000257.4(MYH7):c.2555T>C (p.Met852Thr)

gnomAD frequency: 0.00001  dbSNP: rs397516157

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000557637	SCV000059456	likely pathogenic	Hypertrophic cardiomyopathy	2019-01-31	criteria provided, single submitter	clinical testing	The p.Met852Thr variant in MYH7 has been reported in 5 individuals with HCM (Richard 2003, Morita 2008, Marsiglia 2013, Walsh 2016, LMM unpublished data). This variant has also been identified in 1/15420 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs397516157). Methionine (Met) at position 852 is highly conserved in mammals and across evolutionarily distant species and the change to threonine (Thr) was predicted to be pathogenic using a computational tool clinically validated by our laboratory. This tool's pathogenic prediction is estimated to be correct 94% of the time (Jordan 2011). Additionally, this variant lies in the head region of the protein. Missense variants in this region have been reported and statistically indicated to be more likely to cause disease (Walsh 2016). In summary, although additional studies are required to fully establish its clinical significance, the p.Met852Thr variant is likely pathogenic. ACMG/AMP Criteria applied: PM1; PM2; PP3; PS4_Supporting.
Laboratory of Genetics and Molecular Cardiology, University of São Paulo	RCV000201446	SCV000256148	likely pathogenic	Hypertrophic cardiomyopathy 1		criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000557637	SCV000623672	pathogenic	Hypertrophic cardiomyopathy	2025-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 852 of the MYH7 protein (p.Met852Thr). This variant is present in population databases (rs397516157, gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy and familial left ventricular hypertrophy (PMID: 12707239, 18403758, 24093860, 27247418). ClinVar contains an entry for this variant (Variation ID: 42916). 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.
3billion, Medical Genetics	RCV000201446	SCV002521326	pathogenic	Hypertrophic cardiomyopathy 1	2022-05-22	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.003%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 0.99). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000042916). Different missense changes at the same codon (p.Met852Arg, p.Met852Lys) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000181375, VCV000454357). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002453297	SCV002740169	likely pathogenic	Cardiovascular phenotype	2024-04-11	criteria provided, single submitter	clinical testing	The p.M852T variant (also known as c.2555T>C), located in coding exon 20 of the MYH7 gene, results from a T to C substitution at nucleotide position 2555. The methionine at codon 852 is replaced by threonine, an amino acid with similar properties, and is located in the head domain. This alteration has been detected in multiple individuals with hypertrophic cardiomyopathy (HCM) and was reported to segregate with disease in one small family (Richard P et al. Circulation, 2003 May;107:2227-32; Morita H et al. N. Engl. J. Med., 2008 May;358:1899-908; Marsiglia JD et al. Am. Heart J., 2013 Oct;166:775-82; Walsh R et al. Genet. Med., 2017 02;19:192-203; external communication). This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.