Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001965278 | SCV002212306 | uncertain significance | Brugada syndrome 8 | 2024-03-02 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1004 of the HCN4 protein (p.Pro1004Leu). 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: 1439369). 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. |
| Ambry Genetics | RCV002441082 | SCV002754228 | uncertain significance | Cardiovascular phenotype | 2023-12-17 | criteria provided, single submitter | clinical testing | The c.3011C>T (p.P1004L) alteration is located in exon 8 (coding exon 8) of the HCN4 gene. This alteration results from a C to T substitution at nucleotide position 3011, causing the proline (P) at amino acid position 1004 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |