Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001369750 | SCV001566197 | uncertain significance | Brugada syndrome 8 | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 666 of the HCN4 protein (p.Arg666Gln). This variant is present in population databases (rs781395940, gnomAD 0.01%). This missense change has been observed in individual(s) with bradycardia (PMID: 36244448). ClinVar contains an entry for this variant (Variation ID: 1060332). 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 not expected to disrupt HCN4 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects HCN4 function (PMID: 36244448). 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 | RCV002420823 | SCV002720048 | uncertain significance | Cardiovascular phenotype | 2021-11-22 | criteria provided, single submitter | clinical testing | The p.R666Q variant (also known as c.1997G>A), located in coding exon 7 of the HCN4 gene, results from a G to A substitution at nucleotide position 1997. The arginine at codon 666 is replaced by glutamine, 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. |