Submissions for variant NM_002471.4(MYH6):c.2612G>A (p.Arg871His)

gnomAD frequency: 0.00004  dbSNP: rs869025473

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV000208367	SCV000264070	uncertain significance	Ventricular fibrillation	2015-02-16	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000770452	SCV000901895	uncertain significance	Cardiomyopathy	2016-04-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001069449	SCV001234614	uncertain significance	Hypertrophic cardiomyopathy 14	2024-09-16	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 871 of the MYH6 protein (p.Arg871His). This variant is present in population databases (no rsID available, gnomAD 0.005%). This missense change has been observed in individual(s) with unexplained cardiac arrest (PMID: 28600387). ClinVar contains an entry for this variant (Variation ID: 222715). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt MYH6 protein function with a negative predictive value of 80%. 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.
Ambry Genetics	RCV002426978	SCV002744548	uncertain significance	Cardiovascular phenotype	2023-06-07	criteria provided, single submitter	clinical testing	The p.R871H variant (also known as c.2612G>A), located in coding exon 19 of the MYH6 gene, results from a G to A substitution at nucleotide position 2612. The arginine at codon 871 is replaced by histidine, an amino acid with highly similar properties. This alteration was reported in a sudden cardiac arrest cohort; however, clinical details were limited (Mellor G et al. Circ Cardiovasc Genet, 2017 Jun;10:[Epub ahead of print]). 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.
Fulgent Genetics, Fulgent Genetics	RCV002503821	SCV002816912	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-07-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004734857	SCV005350695	uncertain significance	MYH6-related disorder	2024-05-17	no assertion criteria provided	clinical testing	The MYH6 c.2612G>A variant is predicted to result in the amino acid substitution p.Arg871His. This variant was reported as a variant of uncertain significance in an individual with cardiac arrest (Table S3, Mellor et al. 2017. PubMed ID: 28600387). This variant is reported in 0.0050% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.