Submissions for variant NM_000257.4(MYH7):c.4985G>A (p.Arg1662His)

dbSNP: rs370328209

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035943	SCV000059594	uncertain significance	not specified	2019-08-12	criteria provided, single submitter	clinical testing	The p.Arg1662His variant in MYH7 has been reported in 4 individuals with cardiomyopathy (2 with DCM and 2 with HCM) and did not segeregate with disease in an affected relative in one of the families with HCM (Waldmuller 2011, Kassem 2013, Walsh 2017, LMM data). It has been identified in 0.03% (3/10368) of Ashkenazi Jewish chromosomes and 8/129130 European chromosomes gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PP3.
GeneDx	RCV001719728	SCV000208615	likely benign	not provided	2018-11-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25637381, 23299917, 23233322, 22958901, 21750094, 27532257, 31638223)
Invitae	RCV001050756	SCV001214878	uncertain significance	Hypertrophic cardiomyopathy	2022-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1662 of the MYH7 protein (p.Arg1662His). This variant is present in population databases (rs370328209, gnomAD 0.03%). This missense change has been observed in individual(s) with dilated cardiomyopathy or hypertrophic cardiomyopathy (PMID: 21750094, 23233322, 27532257, 31638223). ClinVar contains an entry for this variant (Variation ID: 43049). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV001184540	SCV001350548	uncertain significance	Cardiomyopathy	2023-02-23	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1662 of the MYH7 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in four individuals affected with hypertrophic cardiomyopathy (PMID: 23233322, 27532257, 31638223, 34137518, 33495597). However, one of these individuals also harbored a splice site variant in the MYBPC3 gene that was associated with disease in the family (PMID: 23233322), and another individual is a carrier of a pathogenic co-variant MYH7 c.2081G>A (p.Arg694His) (ClinVar Variation ID: 264068). This variant has also been reported in one individual affected with dilated cardiomyopathy (PMID: 21750094). This variant has been identified in 16/282816 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Genetics and Genomics Program, Sidra Medicine	RCV001050756	SCV001434149	uncertain significance	Hypertrophic cardiomyopathy		criteria provided, single submitter	research
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001184540	SCV002042688	uncertain significance	Cardiomyopathy	2020-05-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001719728	SCV003817692	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000148703	SCV000190432	uncertain significance	Primary dilated cardiomyopathy	2014-06-01	no assertion criteria provided	research