Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001948092 | SCV002194274 | uncertain significance | Brugada syndrome 8 | 2024-06-11 | criteria provided, single submitter | clinical testing | This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 183 of the HCN4 protein (p.Ser183Trp). This variant is not present in population databases (gnomAD no frequency). 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: 1417232). 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%. 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 | RCV004996107 | SCV005591905 | uncertain significance | Cardiovascular phenotype | 2024-07-11 | criteria provided, single submitter | clinical testing | The p.S183W variant (also known as c.548C>G), located in coding exon 1 of the HCN4 gene, results from a C to G substitution at nucleotide position 548. The serine at codon 183 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. |