Submissions for variant NM_002471.4(MYH6):c.1960C>T (p.Arg654Trp)

gnomAD frequency: 0.00003  dbSNP: rs369938365

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000520542	SCV000619085	uncertain significance	not provided	2023-12-18	criteria provided, single submitter	clinical testing	Reported in an individual with idiopathic ventricular fibrillation and a resuscitated cardiac arrest. The variant was also observed in his three children with sinus node dysfunction and symptom onset in the first year of life, however, the variant was also present in the proband's unaffected mother (PMID: 28491533); 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: 35621855, 34697898, Iskenderov BG[article], 33868385, 28491533)
Agnes Ginges Centre for Molecular Cardiology, Centenary Institute	RCV005054211	SCV001156321	uncertain significance	Left ventricular noncompaction cardiomyopathy; conduction system disease	2018-09-28	criteria provided, single submitter	research	The MYH6 Arg654Trp variant has been identified previously by GeneDx in an infant with ventricular septal defect, left ventricular hypertrophy and heart failure, as well as an adult with ARVC (Pers. Comm). We have also identified this variant in 1 patient with LVNC and another family with conduction anomalies which contribute 2 segregations (Lam L, et al., 2015). The variant is present at a low frequency in the Genome Aggregation Database (MAF=0.000018; http://gnomad.broadinstitute.org/). In silico tools SIFT, PolyPhen2 and MutationTaster predict this variant to be deleterious. Based on the adapted ACMG guidelines (Kelly MA, et al., 2018), this variant is rare (PM2) and in silico tools predict it to be deleterious (PP3) therefore we classify MYH6 Arg654Trp as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001857975	SCV002184597	uncertain significance	Hypertrophic cardiomyopathy 14	2024-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 654 of the MYH6 protein (p.Arg654Trp). This variant is present in population databases (rs369938365, gnomAD 0.004%). This missense change has been observed in individual(s) with arrhythmia (PMID: 28491533). ClinVar contains an entry for this variant (Variation ID: 450490). 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	RCV002420313	SCV002718870	uncertain significance	Cardiovascular phenotype	2024-01-05	criteria provided, single submitter	clinical testing	The p.R654W variant (also known as c.1960C>T), located in coding exon 14 of the MYH6 gene, results from a C to T substitution at nucleotide position 1960. The arginine at codon 654 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been detected in a sudden cardiac arrest survivor, and the variant segregated with sinus node dysfunction in that patient's three children (Lam L et al. HeartRhythm Case Rep, 2015 May;1:141-145). 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000520542	SCV004562469	uncertain significance	not provided	2023-08-31	criteria provided, single submitter	clinical testing	The MYH6 c.1960C>T; p.Arg654Trp variant (rs369938365) is reported in the literature in an individual affected with ventricular fibrillation and three children with sinus node dysfunction, although it was also reported in an unaffected relative (Lam 2015). This variant is found in the general population with an overall allele frequency of 0.002% (6/282,854 alleles) in the Genome Aggregation Database. Computational analyses predict that this variant is deleterious (REVEL: 0.815). However, due to limited information, the clinical significance of the p.Arg654Trp variant is uncertain at this time. References: Lam L et al. Exome sequencing identifies a novel mutation in the MYH6 gene in a family with early-onset sinus node dysfunction, ventricular arrhythmias, and cardiac arrest. HeartRhythm Case Rep. 2015 Apr 30;1(3):141-145. PMID: 28491533.