ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.5593C>T (p.Arg1865Trp)

gnomAD frequency: 0.00003  dbSNP: rs759499155
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute RCV000845390 SCV000987451 uncertain significance not provided criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001858457 SCV002111175 uncertain significance Hypertrophic cardiomyopathy 14 2024-07-30 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 1865 of the MYH6 protein (p.Arg1865Trp). This variant is present in population databases (rs759499155, gnomAD 0.009%). 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: 684811). 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 RCV000845390 SCV002526273 uncertain significance not provided 2022-06-08 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
Ambry Genetics RCV002345929 SCV002648828 uncertain significance Cardiovascular phenotype 2018-11-27 criteria provided, single submitter clinical testing The p.R1865W variant (also known as c.5593C>T), located in coding exon 35 of the MYH6 gene, results from a C to T substitution at nucleotide position 5593. The arginine at codon 1865 is replaced by tryptophan, an amino acid with dissimilar properties. An alternate amino acid substitution at this position, p.R1865Q, was reported in a child with a secundum atrial septal defect, in two of his family members with other structural cardiac findings, and in an unaffected sibling (Granados-Riveron JT et al. Hum. Mol. Genet., 2010 Oct;19:4007-16). 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 RCV002495209 SCV002787047 uncertain significance Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to 2021-10-09 criteria provided, single submitter clinical testing

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