Submissions for variant NM_000257.4(MYH7):c.3667G>A (p.Glu1223Lys)

dbSNP: rs794727410

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176615	SCV000228300	uncertain significance	not provided	2015-01-09	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000415043	SCV000492736	uncertain significance	Primary dilated cardiomyopathy; Epicanthus; Craniosynostosis 4; Delayed speech and language development; Delayed gross motor development; Sagittal craniosynostosis; Muscular ventricular septal defect	2015-05-12	criteria provided, single submitter	clinical testing
GeneDx	RCV000176615	SCV001787723	likely pathogenic	not provided	2023-02-06	criteria provided, single submitter	clinical testing	Identified in patients with DCM referred for genetic testing at GeneDx and in published literature (Horvat et al., 2019; Marschall et al., 2019); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31737537, 29892087)
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798631	SCV002042667	uncertain significance	Cardiomyopathy	2020-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002453630	SCV002615685	uncertain significance	Cardiovascular phenotype	2022-09-19	criteria provided, single submitter	clinical testing	The p.E1223K variant (also known as c.3667G>A), located in coding exon 25 of the MYH7 gene, results from a G to A substitution at nucleotide position 3667. The glutamic acid at codon 1223 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 (Horvat C et al. Genet Med, 2019 01;21:133-143; Marschall C et al. Cardiovasc Diagn Ther, 2019 Oct;9:S292-S298). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV002517699	SCV003484101	uncertain significance	Hypertrophic cardiomyopathy	2023-02-17	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 1223 of the MYH7 protein (p.Glu1223Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 29892087, 31737537). ClinVar contains an entry for this variant (Variation ID: 195928). 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. 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	RCV001798631	SCV004356832	uncertain significance	Cardiomyopathy	2022-10-17	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 1223 of the MYH7 protein. Computational prediction suggests that this variant may have 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: 29892087, 31737537). This variant has not been identified 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.