Submissions for variant NM_000257.4(MYH7):c.2599G>A (p.Glu867Lys)

gnomAD frequency: 0.00003  dbSNP: rs558673680

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151261	SCV000199178	uncertain significance	not specified	2015-07-02	criteria provided, single submitter	clinical testing	The p.Glu867Lys variant in MYH7 has been identified by our laboratory in 1 infan t with RCM and concentric LVH and 1 teenager with ARVC. Both of these individual s carried a second likely pathogenic variant in another gene sufficient to expla in their disease. The p.Gly867Lys variant has also been identified in 1/10402 Af rican chromosomes and 1/11576 Latino chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs558673680). Computational pr ediction tools and conservation analysis do not provide strong support for or ag ainst an impact to the protein. In summary, the clinical significance of the p.G lu867Lys variant is uncertain.
Invitae	RCV000800251	SCV000939952	uncertain significance	Hypertrophic cardiomyopathy	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 867 of the MYH7 protein (p.Glu867Lys). This variant is present in population databases (rs558673680, gnomAD 0.006%). This missense change has been observed in individual(s) with dilated cardiomyopathy (Invitae). ClinVar contains an entry for this variant (Variation ID: 164323). 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%. 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego	RCV000852454	SCV000995147	uncertain significance	Arrhythmogenic right ventricular cardiomyopathy	2019-03-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001177584	SCV001341821	uncertain significance	Cardiomyopathy	2023-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 867 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 not been reported in individuals affected with MYH7-related disorders in the literature. This variant has been identified in 5/282838 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.
Ambry Genetics	RCV002426718	SCV002743298	uncertain significance	Cardiovascular phenotype	2022-10-26	criteria provided, single submitter	clinical testing	The p.E867K variant (also known as c.2599G>A), located in coding exon 20 of the MYH7 gene, results from a G to A substitution at nucleotide position 2599. The glutamic acid at codon 867 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.