Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001367577 | SCV001563931 | uncertain significance | Brugada syndrome 8 | 2023-11-24 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1068 of the HCN4 protein (p.Arg1068Cys). This variant is present in population databases (rs759356193, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1058436). 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 95%. 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, |
RCV002493874 | SCV002784130 | uncertain significance | Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 | 2021-08-17 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV003169870 | SCV003912963 | uncertain significance | Cardiovascular phenotype | 2022-11-01 | criteria provided, single submitter | clinical testing | The p.R1068C variant (also known as c.3202C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 3202. The arginine at codon 1068 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |