Submissions for variant NM_000257.4(MYH7):c.2334C>G (p.Asp778Glu)

dbSNP: rs2069544

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255610	SCV000321915	pathogenic	not provided	2022-03-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency 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: 29121657, 20031602, 11748309, 12707239, 12566107, 28138913, 21896538, 18761664, 27247418, 15114369, 30105547, 31513939, 31737537, 27532257, 29300372, 8343162)
Center for Human Genetics, University of Leuven	RCV000498052	SCV000579522	pathogenic	Hypertrophic cardiomyopathy	2017-02-09	criteria provided, single submitter	clinical testing	ACMG score pathogenic
Invitae	RCV000498052	SCV001211589	pathogenic	Hypertrophic cardiomyopathy	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 778 of the MYH7 protein (p.Asp778Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12566107, 12707239, 21896538, 22112859, 27247418, 29121657). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 265252). 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%. This variant is found within a region of MYH7 between codons 181 and 937 that contains the majority of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). For these reasons, this variant has been classified as Pathogenic.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001170277	SCV001332841	likely pathogenic	Cardiomyopathy	2018-07-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446499	SCV002732979	pathogenic	Cardiovascular phenotype	2020-11-30	criteria provided, single submitter	clinical testing	The p.D778E pathogenic mutation (also known as c.2334C>G), located in coding exon 19 of the MYH7 gene, results from a C to G substitution at nucleotide position 2334. The aspartic acid at codon 778 is replaced by glutamic acid, an amino acid with highly similar properties. This mutation has been reported in several unrelated individuals with hypertrophic cardiomyopathy and has been shown to segregate with hypertrophic cardiomyopathy (HCM) in two of those families (Andersen PS et al. J. Med. Genet. 2001;38:E43; Havndrup O et al. Cardiovasc. Res. 2003;57:347-57; Richard P et al. Circulation. 2003;107:2227-32). The alteration has also been detected in the homozygous state in two related individuals with HCM who suffered sudden death at a young age (Richard P et al. Circulation. 2003;107:2227-32). An alteration resulting in the same amino acid change (c.2443C>A p.D778E) and several other alterations at the same codon (p.D778V and p.D778G) have also been associated with HCM (Harada H et al. Biochem. Biophys. Res. Commun. 1993;194:791-8; Van Driest SL et al. J. Am. Coll. Cardiol. 2004;44:602-10; Otsuka H et al. Circ. J. 2012;76:453-61). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000255610	SCV001740177	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000255610	SCV001928157	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000255610	SCV001966863	likely pathogenic	not provided		no assertion criteria provided	clinical testing