Submissions for variant NM_002471.4(MYH6):c.2717G>A (p.Arg906His)

dbSNP: rs527636904

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001700883	SCV002050501	uncertain significance	not provided	2021-06-28	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 946324; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 27535533)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001866269	SCV002176626	uncertain significance	Hypertrophic cardiomyopathy 14	2024-04-18	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 906 of the MYH6 protein (p.Arg906His). This variant is present in population databases (rs527636904, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with MYH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 1284635). 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 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	RCV002425024	SCV002744308	uncertain significance	Cardiovascular phenotype	2023-11-01	criteria provided, single submitter	clinical testing	The p.R906H variant (also known as c.2717G>A), located in coding exon 20 of the MYH6 gene, results from a G to A substitution at nucleotide position 2717. The arginine at codon 906 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in two individuals from a cardiomyopathy genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). 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	RCV002488471	SCV002777350	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-08-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323917	SCV004029428	likely benign	not specified	2023-07-22	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV001700883	SCV001925019	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001700883	SCV001958623	uncertain significance	not provided		no assertion criteria provided	clinical testing