Submissions for variant NM_000257.4(MYH7):c.2052G>A (p.Met684Ile)

dbSNP: rs727503262

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151281	SCV000199212	likely benign	not specified	2015-11-09	criteria provided, single submitter	clinical testing	p.Met684Ile in exon 19 of MYH7: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, >20 mammals have an isoleucine (Ile) at this position. It has been identifi ed in 1/65670 European chromosomes by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org, dbSNP rs727503262).
Eurofins Ntd Llc (ga)	RCV000724274	SCV000226728	uncertain significance	not provided	2015-01-05	criteria provided, single submitter	clinical testing
Invitae	RCV000685085	SCV000812557	uncertain significance	Hypertrophic cardiomyopathy	2023-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 684 of the MYH7 protein (p.Met684Ile). This variant is present in population databases (rs727503262, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MYH7-related conditions. ClinVar contains an entry for this variant (Variation ID: 164349). 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 not expected to disrupt MYH7 protein function. 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). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845324	SCV000987370	uncertain significance	Primary familial dilated cardiomyopathy		criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798473	SCV002042262	uncertain significance	Cardiomyopathy	2020-07-24	criteria provided, single submitter	clinical testing