Submissions for variant NM_002471.4(MYH6):c.5594G>A (p.Arg1865Gln)

gnomAD frequency: 0.00004  dbSNP: rs138720701

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000623148	SCV000740613	uncertain significance	Primary familial hypertrophic cardiomyopathy	2016-08-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688532	SCV000816148	uncertain significance	Hypertrophic cardiomyopathy 14	2025-01-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1865 of the MYH6 protein (p.Arg1865Gln). This variant is present in population databases (rs138720701, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital heart defects (PMID: 20656787). ClinVar contains an entry for this variant (Variation ID: 520531). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV002343177	SCV002649157	uncertain significance	Cardiovascular phenotype	2024-08-19	criteria provided, single submitter	clinical testing	The p.R1865Q variant (also known as c.5594G>A), located in coding exon 35 of the MYH6 gene, results from a G to A substitution at nucleotide position 5594. The arginine at codon 1865 is replaced by glutamine, an amino acid with highly similar properties. This alteration was detected in an individual with a secundum atrial septal defect, as well as in his mother with dilated inferior vena cava, in his brother with a small ventricular septal defect that closed spontaneously, and in his unaffected sister; of note, MYH6 was the only gene tested in this family (Granados-Riveron JT et al. Hum. Mol. Genet., 2010 Oct;19:4007-16). This alteration has also been reported in a hypertrophic cardiomyopathy (HCM) cohort; however, clinical details were limited (Lopes LR et al. Heart, 2015 Feb;101:294-301). 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	RCV002477362	SCV002780063	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-10-16	criteria provided, single submitter	clinical testing
GeneDx	RCV003314627	SCV004014575	uncertain significance	not provided	2024-03-13	criteria provided, single submitter	clinical testing	Identified in a patient with hypertrophic cardiomyopathy (HCM) who harbored an additional cardiogenetic variant and in a patient with secundum atrial septal defect (PMID: 23396983, 20656787); 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: 25351510, 20656787, 29762087, 35621855, 22955375, 29687901, 23396983)
PreventionGenetics, part of Exact Sciences	RCV004533291	SCV004750656	uncertain significance	MYH6-related disorder	2023-12-20	no assertion criteria provided	clinical testing	The MYH6 c.5594G>A variant is predicted to result in the amino acid substitution p.Arg1865Gln. This variant was reported in an individual with hypertrophic cardiomyopathy (Table S1, Lopes et al. 2013. PubMed ID: 23396983). This variant was also reported in a family with a wide spectrum of congenital heart defects, including atrial septal defect, ventricular septal defect, and dilated inferior vena cava. However, this variant was also identified in an unaffected family member (Granados-Riveron et al. 2010. PubMed ID: 20656787). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.