Submissions for variant NM_000257.4(MYH7):c.5030G>A (p.Arg1677His)

gnomAD frequency: 0.00001  dbSNP: rs730880914

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000158869	SCV000208804	uncertain significance	not provided	2016-08-12	criteria provided, single submitter	clinical testing	The R1677H variant in the MYH7 gene was first identified via direct sequencing of the MYBPC3 and MYH7 genes in two individuals with DCM (Waldmuller et al., 2011). This variant was also identified in the heterozygous state in another individual with DCM who was evaluated with a multi-gene panel (Berge et al., 2014). However, for all reported individuals, additional clinical information, familial segregation information, and in vitro functional studies were not included. The R1677H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The R1677H 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. Therefore, it is unclear if R1677H is a pathogenic or benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799550	SCV000939218	uncertain significance	Hypertrophic cardiomyopathy	2023-09-03	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 181393). This missense change has been observed in individual(s) with dilated cardiomyopathy and left ventricular noncompaction (PMID: 21750094, 24111713, 30188508). This variant is present in population databases (rs730880914, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1677 of the MYH7 protein (p.Arg1677His).
Color Diagnostics, LLC DBA Color Health	RCV001176078	SCV001339916	uncertain significance	Cardiomyopathy	2023-04-25	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1677 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 21750094), in an individual affected with hypertrophic cardiomyopathy (PMID: 24111713, 28971120), and in an individual affected with left ventricular noncompaction (PMID: 30188508). This variant has been identified in 6/282764 chromosomes 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.
Genetics and Genomics Program, Sidra Medicine	RCV001293063	SCV001434045	uncertain significance	Primary dilated cardiomyopathy		criteria provided, single submitter	research
Ambry Genetics	RCV002336365	SCV002642999	uncertain significance	Cardiovascular phenotype	2021-11-29	criteria provided, single submitter	clinical testing	The p.R1677H variant (also known as c.5030G>A), located in coding exon 33 of the MYH7 gene, results from a G to A substitution at nucleotide position 5030. The arginine at codon 1677 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in cardiomyopathy cohorts, as well as sudden unexplained death cohorts; however, clinical details were limited (Waldmüller S et al. Eur J Heart Fail, 2011 Nov;13:1185-92; Berge KE et al. Clin Genet, 2014 Oct;86:355-60; Dejgaard LA et al. Data Brief, 2017 Dec;15:30-39; Dewar LJ et al. Circ Cardiovasc Genet, 2017 Aug;10:[ePub ahead of print]; Takasaki A et al. Pediatr Res, 2018 11;84:733-742). 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	RCV002498790	SCV002781224	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	2021-11-09	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004528899	SCV004106270	uncertain significance	MYH7-related disorder	2022-12-04	criteria provided, single submitter	clinical testing	The MYH7 c.5030G>A variant is predicted to result in the amino acid substitution p.Arg1677His. This variant was reported in individuals with dilated cardiomyopathy, hypertrophic cardiomyopathy, or left ventricular noncompaction (Table S1, Waldmüller et al. 2011. PubMed ID: 21750094; Bergeet al. 2014. PubMed ID: 24111713; Dejgaard et al. 2017. PubMed ID: 28971120; Table S3, Takasaki et al. 2018. PubMed ID: 30188508; Table S5, Hirono et al. 2020. PubMed ID: 32600061). However, this variant was also documented in the general population (Table S2, Dewar et al. 2017. PubMed ID: 28807990; Table S6, Park et al. 2022. PubMed ID: 34542152). This variant is reported in 0.0046% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23884965-C-T) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181393/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV001176078	SCV004829632	uncertain significance	Cardiomyopathy	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1677 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with dilated cardiomyopathy (PMID: 21750094), in an individual affected with hypertrophic cardiomyopathy (PMID: 24111713, 28971120), and in an individual affected with left ventricular noncompaction (PMID: 30188508). This variant has been identified in 6/282764 chromosomes 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.