Submissions for variant NM_000257.4(MYH7):c.3856G>A (p.Glu1286Lys)

gnomAD frequency: 0.00001  dbSNP: rs397516196

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035871	SCV000059522	uncertain significance	not specified	2020-04-19	criteria provided, single submitter	clinical testing	The Glu1286Lys variant in MYH7 has been reported in two young children with dilated cardiomyopathy (DCM), one of whom carried another variant that likely contributed to disease severity (Lakdawala 2012 PMID:22464770, Walsh 2017 PMID:27532257, LMM data). This variant has also been reported by another clinical laboratory in ClinVar (Variation ID: 42978) and has been identified in 0.003% (3/113766) of European chromosomes in 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: PS4_Supporting, PM2, PP3.
Invitae	RCV000628955	SCV000749863	uncertain significance	Hypertrophic cardiomyopathy	2023-06-17	criteria provided, single submitter	clinical testing	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 42978). This missense change has been observed in individuals with dilated cardiomyopathy (PMID: 22464770, 27532257). This variant is present in population databases (rs397516196, gnomAD 0.003%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1286 of the MYH7 protein (p.Glu1286Lys).
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198766	SCV001369761	uncertain significance	Congenital myopathy with fiber type disproportion	2020-01-20	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP2,PP3.
Color Diagnostics, LLC DBA Color Health	RCV001525525	SCV001735664	uncertain significance	Cardiomyopathy	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1286 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 22464770, 27532257, 31983221). This variant has been identified in 3/251488 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.
Revvity Omics, Revvity	RCV003129764	SCV003817677	uncertain significance	not provided	2021-10-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001525525	SCV004820445	uncertain significance	Cardiomyopathy	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1286 of the MYH7 protein. Computational prediction suggests that this variant may have a deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with dilated cardiomyopathy (PMID: 22464770, 27532257, 31983221). This variant has been identified in 3/251488 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	RCV004018776	SCV005033923	uncertain significance	Cardiovascular phenotype	2024-01-24	criteria provided, single submitter	clinical testing	The p.E1286K variant (also known as c.3856G>A), located in coding exon 27 of the MYH7 gene, results from a G to A substitution at nucleotide position 3856. The glutamic acid at codon 1286 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in dilated cardiomyopathy (DCM) cohorts; however, clinical details were limited (Walsh R et al. Genet Med, 2017 Feb;19:192-203; Perret C et al. Clin Genet, 2024 Feb;105:185-189). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.