ClinVar Miner

Submissions for variant NM_002471.4(MYH6):c.4823G>A (p.Arg1608His)

gnomAD frequency: 0.00001  dbSNP: rs747494958
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000414669 SCV000492152 uncertain significance not specified 2016-12-14 criteria provided, single submitter clinical testing The R1608H variant in the MYH6 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The R1608H variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1608H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs in the coiled coil region, at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, we interpret R1608H as a variant of uncertain significance
Ambry Genetics RCV002338973 SCV002637912 uncertain significance Cardiovascular phenotype 2021-11-28 criteria provided, single submitter clinical testing The p.R1608H variant (also known as c.4823G>A), located in coding exon 31 of the MYH6 gene, results from a G to A substitution at nucleotide position 4823. The arginine at codon 1608 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is conserved. 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.
Fulgent Genetics, Fulgent Genetics RCV002481280 SCV002783279 uncertain significance Hypertrophic cardiomyopathy 1; Dilated cardiomyopathy 1EE; Hypertrophic cardiomyopathy 14; Atrial septal defect 3; Sick sinus syndrome 3, susceptibility to 2021-09-16 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003514352 SCV004366294 uncertain significance Hypertrophic cardiomyopathy 14 2023-11-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1608 of the MYH6 protein (p.Arg1608His). This variant is present in population databases (rs747494958, gnomAD 0.006%). 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: 373551). 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.

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