Submissions for variant NM_000257.4(MYH7):c.1700G>A (p.Arg567His)

gnomAD frequency: 0.00001  dbSNP: rs377491278

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Cardiomyopathy Variant Curation Expert Panel	RCV000035741	SCV001976475	uncertain significance	Primary dilated cardiomyopathy	2021-09-27	reviewed by expert panel	curation	The c.1700G>A (p.Arg567His) variant in MYH7 has been identified in 3 individuals with DCM, 1 of whom also had an additional variant in another DCM-associated gene (PS4_Supporting; Pugh 2014 PMID:24503780; Walsh 2017 PMID:27532257; GeneDx pers. comm., LMM pers. comm.) and segregated with disease in 3 affected relatives with DCM from 1 family (PP1; LMM pers. comm.). Additionally, this variant has also been reported in an individual with neuropathy and unspecified heart disease who also had an additional variant in a gene that could account for the clinical features observed (Invitae pers. comm.). This variant has been identified in 0.003% (1/30616) of South Asian chromosomes (PM2; http://gnomad.broadinstitute.org, v2.1.1). This variant lies in the head region of the protein (aa 181-937) and while missense variants in this region are statistically more likely to be associated with HCM (Walsh 2017 PMID:27532257), location in this region cannot be used to support pathogenicity for other phenotypes; therefore, PM1 is not applicable. Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, due to insufficient evidence, this variant is classified as uncertain significance for dilated cardiomyopathy in an autosomal dominant manner. MYH7-specific ACMG/AMP criteria applied (Kelly 2018 PMID:29300372): PS4_Supporting; PP1; PM2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035741	SCV000059392	likely pathogenic	Primary dilated cardiomyopathy	2014-04-04	criteria provided, single submitter	clinical testing	proposed classification - variant undergoing re-assessment, contact laboratory
Invitae	RCV000799659	SCV000939333	uncertain significance	Hypertrophic cardiomyopathy	2024-01-16	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 567 of the MYH7 protein (p.Arg567His). This variant is present in population databases (rs377491278, gnomAD 0.003%). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 24503780, 27532257). ClinVar contains an entry for this variant (Variation ID: 42860). 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%. 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.
GeneDx	RCV003223608	SCV003919423	likely pathogenic	not provided	2023-04-11	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: 27532257, 31447099, 24503780, 29300372)
Ambry Genetics	RCV003298054	SCV003993379	uncertain significance	Cardiovascular phenotype	2023-06-04	criteria provided, single submitter	clinical testing	The p.R567H variant (also known as c.1700G>A), located in coding exon 14 of the MYH7 gene, results from a G to A substitution at nucleotide position 1700. The arginine at codon 567 is replaced by histidine, an amino acid with highly similar properties. This variant has been detected in individuals with dilated cardiomyopathy (DCM) with and without features of noncompaction, some of whom had variants in other cardiomyopathy-related genes, and was reported to segregate with disease in a family with DCM (Pugh TJ et al. Genet Med, 2014 Aug;16:601-8; external communication). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003486554	SCV004239442	likely pathogenic	Cardiomyopathy	2023-05-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003223608	SCV005042491	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing