Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000818121 | SCV000958718 | uncertain significance | Brugada syndrome 8 | 2024-01-04 | 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 330 of the HCN4 protein (p.Pro330Leu). This variant is present in population databases (rs370442588, gnomAD 0.006%). This missense change has been observed in individual(s) with generalized epilepsy (PMID: 30986657). ClinVar contains an entry for this variant (Variation ID: 660833). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on HCN4 protein function. 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 | RCV002381845 | SCV002695821 | uncertain significance | Cardiovascular phenotype | 2022-02-02 | criteria provided, single submitter | clinical testing | The p.P330L variant (also known as c.989C>T), located in coding exon 2 of the HCN4 gene, results from a C to T substitution at nucleotide position 989. The proline at codon 330 is replaced by leucine, an amino acid with similar properties. This alteration was reported in an individual with generalized epilepsy; however, it was also identified in two unaffected children (DiFrancesco JC et al. Epilepsy Res, 2019 07;153:49-58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |