Submissions for variant NM_000257.4(MYH7):c.2069T>C (p.Met690Thr) (rs397516128)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine,Partners HealthCare 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	2018-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces methionine with threonine at codon 690 of the MYH7 protein (p.Met690Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with hypertrophic cardiomyopathy (PMID: 27532257, 27247418, 25524337). ClinVar contains an entry for this variant (Variation ID: 42876). A computational algorithm designed to assess the pathogenicity of variants in MYH7 with regard to hypertrophic cardiomyopathy predicted this sequence change to be deleterious. The algorithm has a sensitivity of 94% and a specificity of 89% (PMID: 21310275). 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