Submissions for variant NM_000257.4(MYH7):c.2081G>A (p.Arg694His)

gnomAD frequency: 0.00003  dbSNP: rs886039030

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000249009	SCV000319723	likely pathogenic	Cardiovascular phenotype	2023-04-13	criteria provided, single submitter	clinical testing	The p.R694H variant (also known as c.2081G>A), located in coding exon 17 of the MYH7 gene, results from a G to A substitution at nucleotide position 2081. The arginine at codon 694 is replaced by histidine, an amino acid with some similar properties. This alteration has been reported in several patients from hypertrophic cardiomyopathy (HCM) and sudden death cohorts (Erdmann J et al. Clin Genet. 2003;64(4):339-49; Berge KE and Leren TP. Clin Genet. 2014;86(4):355-60; Lopes LR et al. Heart. 2015;101(4):294-301. Jiménez-Jáimez et al. J. Rev Esp Cardiol (Engl Ed). 2017;70(10):808-816; GeneDx pers. comm.; Invitae pers. comm.; Ambry internal data). 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). In addition, this variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Other alterations at the same codon, p.R694C (c.2080C>T) and p.R694L (c.2081G>T), have also been reported in association with HCM with variable penetrance (Andersen PS et al. Clin Genet. 1999;56(3):244-6; Zheng DD et al. J Int Med Res. 2010;38(3):810-20). 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.
GeneDx	RCV000422742	SCV000513801	likely pathogenic	not provided	2022-05-31	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: 28566242, 20819418, 12974739, 25351510, 27532257, 24111713, 31638223, 29300372, 34542152)
Invitae	RCV000628874	SCV000749782	pathogenic	Hypertrophic cardiomyopathy	2023-08-28	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 694 of the MYH7 protein (p.Arg694His). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with hypertrophic cardiomyopathy (PMID: 12974739, 20819418, 24111713, 25351510, 27532257). ClinVar contains an entry for this variant (Variation ID: 264068). 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.
Color Diagnostics, LLC DBA Color Health	RCV001191924	SCV001359860	likely pathogenic	Cardiomyopathy	2023-03-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 694 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). This variant is found within a highly conserved region of the myosin head domain. Missense variants in this region have been shown to be significantly overrepresented in individuals with hypertrophic cardiomyopathy (PMID: 27532257). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with hypertrophic cardiomyopathy (PMID: 12974739, 23197161, 25351510, 27532257, 28566242, 33495596). This variant has been shown mild, later-onset hypertrophic cardiomyopathy in a Chinese family (PMID: 20819418). This variant has been identified in 3/282754 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different missense variant occurring at the same codon, p.Arg694Cys, is considered to be disease-causing (ClinVar variation ID: 177627), indicating that arginine at this position is important for MYH7 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV002503962	SCV002813830	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	2021-11-30	criteria provided, single submitter	clinical testing