ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs397516157
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
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variant in MYH7 has been reported in 5 individuals with HCM (Richard 2003, Morita 2008, Marsiglia 2013, Walsh 2016, LMM unpublished data).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,; 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
Invitae RCV000557637 SCV000623672 pathogenic Hypertrophic cardiomyopathy 2022-04-11 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). An algorithm developed specifically for the MYH7 gene suggests that this missense change is likely to be deleterious (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). For these reasons, this variant has been classified as Pathogenic.
3billion 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 2020-08-04 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; Invitae pers. comm.; OMGL pers. comm.). This allele was reported in one heterozygous individual in population-based cohorts in the Genome Aggregation Database (gnomAD). 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.