Submissions for variant NM_000257.4(MYH7):c.5530G>A (p.Glu1844Lys)

gnomAD frequency: 0.00001  dbSNP: rs730880821

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV001618315	SCV001842657	uncertain significance	Primary dilated cardiomyopathy	2021-10-05	reviewed by expert panel	curation	The c.5530G>A (p.Glu1844Lys) variant in MYH7 has been reported in 2 individuals with DCM, 1 individual with HCM and in 1 individual with LVNC (PS4_supporting; Walsh 2017 PMID:27532257, GeneDx pers. comm.). This variant has been identified in 0.0099% (1/10078) of Ashkenazi Jewish chromosomes, but is absent from all other populations in gnomAD v2.1.1 (PM2; http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis suggest that this variant may impact the protein (PP3). In summary, due to lack of sufficient evidence, this variant meets criteria to be classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PP3; PM2; PS4_Supporting
GeneDx	RCV000158706	SCV000208641	likely pathogenic	not provided	2014-12-29	criteria provided, single submitter	clinical testing	The Glu1844Lys variant in the MYH7 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Glu1844Lys results in a non-conservative amino acid substitution of a negatively charged Glutamic acid with a positively charged Lysine at a position that is conserved across species. In silico analysis predicts Glu1844Lys is damaging to the protein structure/function. Mutations in nearby residues (Ser1836Leu, Arg1845Trp, Arg1846Cys, Thr1854Met) have been reported in association with cardiomyopathy, further supporting the functional importance of this region of the protein. Furthermore, the Glu1844Lys variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. In summary, while Glu1844Lys is a good candidate for a disease-causing mutation, with the clinical and molecular information available at this time we cannot unequivocally determine the clinical significance of this variant. The variant is found in DCM panel(s).
Invitae	RCV000469554	SCV000546202	uncertain significance	Hypertrophic cardiomyopathy	2023-08-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 181285). 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. 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. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 27532257). This variant is present in population databases (rs730880821, gnomAD 0.01%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1844 of the MYH7 protein (p.Glu1844Lys).
AiLife Diagnostics, AiLife Diagnostics	RCV000158706	SCV002502406	uncertain significance	not provided	2021-09-22	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002345541	SCV002653712	uncertain significance	Cardiovascular phenotype	2021-12-01	criteria provided, single submitter	clinical testing	The p.E1844K variant (also known as c.5530G>A), located in coding exon 35 of the MYH7 gene, results from a G to A substitution at nucleotide position 5530. The glutamic acid at codon 1844 is replaced by lysine, an amino acid with similar properties. This variant was detected in a cardiomyopathy genetic testing cohort; however clinical details were not provided (Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002505189	SCV002803246	uncertain significance	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2021-11-02	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000158706	SCV003815401	uncertain significance	not provided	2020-10-08	criteria provided, single submitter	clinical testing