Submissions for variant NM_002471.4(MYH6):c.161G>A (p.Arg54Gln)

gnomAD frequency: 0.00010  dbSNP: rs727503239

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000151226	SCV000199093	uncertain significance	not specified	2013-04-09	criteria provided, single submitter	clinical testing	The Arg54Gln variant in MYH6 has been identified by our laboratory in 1 Caucasia n infant with DCM (LMM unpublished data). This variant has also been identified in large European American and African American populations by the NHLBI Exome S equencing Project (http://evs.gs.washington.edu/EVS), though it may be present i n other populations. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. At this time, additional studies are needed to fully assess the clinical significance of this variant.
Blueprint Genetics	RCV000208506	SCV000264065	uncertain significance	Primary familial hypertrophic cardiomyopathy	2014-12-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001321909	SCV001512760	uncertain significance	Hypertrophic cardiomyopathy 14	2024-06-03	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 54 of the MYH6 protein (p.Arg54Gln). This variant is present in population databases (rs727503239, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of MYH6-related conditions (PMID: 30403391). ClinVar contains an entry for this variant (Variation ID: 164257). 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 MYH6 protein function with a positive 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.
GeneDx	RCV000995139	SCV001784537	uncertain significance	not provided	2024-08-06	criteria provided, single submitter	clinical testing	Identified in a patient with LQTS and SCA in published literature (PMID: 30403391); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30403391)
Ambry Genetics	RCV002390325	SCV002703226	uncertain significance	Cardiovascular phenotype	2023-06-15	criteria provided, single submitter	clinical testing	The p.R54Q variant (also known as c.161G>A), located in coding exon 1 of the MYH6 gene, results from a G to A substitution at nucleotide position 161. The arginine at codon 54 is replaced by glutamine, an amino acid with highly similar properties. This variant has been detected in a sudden cardiac arrest cohort in an individual reported to have long QT syndrome; however, details were limited (Stpie-Wojno M et al. Pol Arch Intern Med. 2018 Dec 21;128(12):721-730). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV002498699	SCV002785284	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-08-23	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000995139	SCV001925754	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000995139	SCV001932710	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000995139	SCV001972540	uncertain significance	not provided		no assertion criteria provided	clinical testing