Submissions for variant NM_000257.4(MYH7):c.2069T>C (p.Met690Thr)

dbSNP: rs397516128

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000628835	SCV001976476	uncertain significance	Hypertrophic cardiomyopathy	2021-09-22	reviewed by expert panel	curation	The c.2069T>C (p.Met690Thr) variant in MYH7 has been reported in at least 3 individuals with HCM (PS4_Supporting; Coppini 2014 PMID:25524337; Homberger 2016 PMID:27247418; Weissler-Snir 2017 PMID:28193612; Walsh 2017 PMID:27532257; CHEO pers. comm.; LMM pers. comm.; OMGL pers. comm.). This variant was absent from large population studies (PM2; http://gnomad.broadinstitute.org, v2.1.1). 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 associated with HCM (PM1; Walsh 2017 PMID:27532257). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). Based on criteria selected, this variant would be classified as likely pathogenic; however the expert panel deemed the bulk of available evidence as being derived from predictive models. Therefore, in the absence of additional case or segregation data, this variant is classified as uncertain significance for hypertrophic cardiomyopathy in an autosomal dominant manner. ACMG/AMP Criteria applied: PS4_Supporting; PM2; PM1; PP3.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000628835	SCV000059410	likely pathogenic	Hypertrophic cardiomyopathy	2018-11-30	criteria provided, single submitter	clinical testing	The p.Met690Thr variant in MYH7 has been reported in at least 2 individuals with HCM (Coppini 2014, Homburger 2016, Walsh 2017, LMM data). This variant has also been reported by another clinical laboratory in ClinVar (Variation ID 42876) an d was absent from large population studies. This variant was predicted to be pat hogenic 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, the p.Met690Thr variant is located in the head domain of th e MYH7 protein, where studies have shown that missense variants in this region h ave been reported and statistically indicated to be more likely to cause disease (Walsh 2017). In summary, although additional studies are required to fully est ablish its clinical significance, this variant meets criteria to be classified a s likely pathogenic for autosomal dominant HCM. ACMG/AMP criteria applied: PM1, PM2, PP3, PS4_Supporting.
Invitae	RCV000628835	SCV000749742	pathogenic	Hypertrophic cardiomyopathy	2023-11-03	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 690 of the MYH7 protein (p.Met690Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 25524337, 27247418, 27532257). ClinVar contains an entry for this variant (Variation ID: 42876). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770494	SCV000901939	uncertain significance	Cardiomyopathy	2016-10-17	criteria provided, single submitter	clinical testing