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	uncertain significance	Hypertrophic cardiomyopathy	2023-02-06	criteria provided, single submitter	clinical testing	The p.Met690Thr variant in MYH7 has been reported in at least 3 individuals with hypertrophic cardiomyopathy (HCM) and segregated with disease in 1 affected relative from 1 family (Coppini 2014 PMID:25524337; Homburger 2016 PMID:27247418; Walsh 2017 PMID:27532257; Marschall 2019 PMID:31737537, LMM data). It was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. This variant lies in the head region of the protein and missense variants in this region are statistically more likely to be disease-associated (Walsh 2017 PMID 27532257). Moreover, this variant was classified as Uncertain Significance on September 22, 2021 by the ClinGen-approved Cardiomyopathy expert panel (Variation ID 42876). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM1, PS4_Supporting, PM2_Supporting, PP3.
Labcorp Genetics (formerly Invitae), Labcorp	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