ClinVar Miner

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

gnomAD frequency: 0.00006  dbSNP: rs111473291
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Total submissions: 7
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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 2017-02-06 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the MYH6 gene. The R1820W variant has not been published as pathogenic or been reported as benign to our knowledge. The R1820W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. However, to our knowledge no studies have been performed to determine the functional effect of the R1820W variant. Furthermore, the Exome Aggregation Consortium (ExAC) reports R1820W was observed in 8/10,400 alleles from individuals of African ancestry (Lek et al., 2016).
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, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001055045 SCV001219409 uncertain significance Hypertrophic cardiomyopathy 14 2023-05-31 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 228897). This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 32746448). This variant is present in population databases (rs111473291, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. 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).
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
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

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