Submissions for variant NM_000257.4(MYH7):c.2788G>C (p.Glu930Gln)

dbSNP: rs397516171

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000695329	SCV000199164	likely pathogenic	Hypertrophic cardiomyopathy	2013-02-15	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
GeneDx	RCV000158575	SCV000208510	pathogenic	not provided	2023-02-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27247418, 18533079, 16858239, 27532257, 28606303, 21310275, 19134269, 29212898, 32746448, 34542152, 33906374, 29300372)
Fulgent Genetics, Fulgent Genetics	RCV000515259	SCV000611213	pathogenic	Hypertrophic cardiomyopathy 1; Myopathy, myosin storage, autosomal recessive; Myosin storage myopathy; Congenital myopathy with fiber type disproportion; Dilated cardiomyopathy 1S; MYH7-related skeletal myopathy	2022-01-10	criteria provided, single submitter	clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000158575	SCV000740378	likely pathogenic	not provided	2017-06-26	criteria provided, single submitter	clinical testing
Invitae	RCV000695329	SCV000823821	pathogenic	Hypertrophic cardiomyopathy	2023-07-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 930 of the MYH7 protein (p.Glu930Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 18533079, 27247418, 27532257; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 164312). 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 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	RCV001798472	SCV002042656	pathogenic	Cardiomyopathy	2021-08-09	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147351	SCV003835251	pathogenic	Myopathy, myosin storage, autosomal recessive	2022-10-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147350	SCV003835738	pathogenic	Hypertrophic cardiomyopathy 1	2022-10-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003320108	SCV003835739	pathogenic	Myosin storage myopathy	2022-10-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147346	SCV003835789	pathogenic	Dilated cardiomyopathy 1S	2022-10-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003147349	SCV003835807	pathogenic	MYH7-related skeletal myopathy	2022-10-16	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003320108	SCV003835862	pathogenic	Myosin storage myopathy	2022-10-16	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004532676	SCV004740279	pathogenic	MYH7-related disorder	2024-01-15	criteria provided, single submitter	clinical testing	The MYH7 c.2788G>C variant is predicted to result in the amino acid substitution p.Glu930Gln. This variant was reported in multiple individuals with hypertrophic cardiomyopathy and left ventricular noncompaction (Girolami et al. 2006. PubMed ID: 16858239; Table S1B, Walsh et al. 2017. PubMed ID: 27532257; Miller et al. 2017. PubMed ID: 29212898; Table S2, Burstein et al. 2021. PubMed ID: 32746448; Table S6, Park et al. 2022. PubMed ID: 34542152). This variant has not been reported in a large population database, indicating this variant is rare. A different nucleotide substitution affecting the same amino acid (p.Glu930Lys) has been reported in individuals with hypertrophic cardiomyopathy (Table S1B, Walsh et al. 2017. PubMed ID: 27532257). Taken together, the c.2788G>C (p.Glu930Gln) variant is interpreted as pathogenic.
Ambry Genetics	RCV004019817	SCV005033895	likely pathogenic	Cardiovascular phenotype	2023-11-08	criteria provided, single submitter	clinical testing	The p.E930Q variant (also known as c.2788G>C), located in coding exon 21 of the MYH7 gene, results from a G to C substitution at nucleotide position 2788. The glutamic acid at codon 930 is replaced by glutamine, an amino acid with highly similar properties. This alteration is located in the myosin head domain, which contains a statistically significant clustering of pathogenic missense variants (Homburger JR et al. Proc Natl Acad Sci U S A, 2016 06;113:6701-6; Walsh R et al. Genet Med, 2017 02;19:192-203; Ambry internal data). This alteration has been reported in several individuals with hypertrophic cardiomyopathy (HCM) (Girolami F et al. J Cardiovasc Med (Hagerstown), 2006 Aug;7:601-7; Olivotto I et al. Mayo Clin Proc, 2008 Jun;83:630-8; Alfares AA et al. Genet Med, 2015 Nov;17:880-8; Walsh R et al. Genet Med, 2017 Feb;19:192-203; Ware SM et al. J Am Heart Assoc, 2021 May;10:e017731; Burstein DS et al. Pediatr Res, 2021 May;89:1470-1476; Park J et al. Hum Mol Genet, 2022 Mar;31:827-837). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic.