Submissions for variant NM_002471.4(MYH6):c.5458C>T (p.Arg1820Trp)

gnomAD frequency: 0.00006  dbSNP: rs111473291

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000216487	SCV000272030	uncertain significance	not specified	2015-05-19	criteria provided, single submitter	clinical testing	The p.Arg1820Trp variant in MYH6 has not been previously reported in individuals with cardiomyopathy, but has been identified in 0.1% (8/10400) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs111473291). Computational prediction tools and conservation analysis s uggest that the variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, the clinical significan ce of the p.Arg1820Trp variant is uncertain.
GeneDx	RCV000766294	SCV000573046	uncertain significance	not provided	2024-03-28	criteria provided, single submitter	clinical testing	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: 31983221, 32746448)
Ambry Genetics	RCV000617563	SCV000735371	uncertain significance	Cardiovascular phenotype	2022-07-28	criteria provided, single submitter	clinical testing	The p.R1820W variant (also known as c.5458C>T), located in coding exon 34 of the MYH6 gene, results from a C to T substitution at nucleotide position 5458. The arginine at codon 1820 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in a dilated cardiomyopathy (DCM) cohort; however, clinical details were limited (Burstein DS et al. Pediatr Res, 2021 05;89:1470-1476). This amino acid position is well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001055045	SCV001219409	uncertain significance	Hypertrophic cardiomyopathy 14	2024-06-17	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 1820 of the MYH6 protein (p.Arg1820Trp). This variant is present in population databases (rs111473291, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32746448). ClinVar contains an entry for this variant (Variation ID: 228897). 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.
Fulgent Genetics, Fulgent Genetics	RCV002485393	SCV002793538	uncertain significance	Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to	2021-11-22	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000766294	SCV005192254	uncertain significance	not provided		criteria provided, single submitter	not provided
Clinical Genetics, Academic Medical Center	RCV000766294	SCV001921995	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000766294	SCV001962966	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004541340	SCV004776856	uncertain significance	MYH6-related disorder	2023-10-23	no assertion criteria provided	clinical testing	The MYH6 c.5458C>T variant is predicted to result in the amino acid substitution p.Arg1820Trp. This variant was reported as uncertain significance in an individual with dilated cardiomyopathy (Table S2, Burstein et al. 2021. PubMed ID: 32746448). This variant is reported in 0.072% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-23853758-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.