Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000694706 | SCV000823163 | uncertain significance | Brugada syndrome 8 | 2024-01-11 | 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 776 of the HCN4 protein (p.Pro776Leu). This variant is present in population databases (no rsID available, gnomAD 0.0008%). 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: 573123). 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 | RCV002442459 | SCV002732463 | uncertain significance | Cardiovascular phenotype | 2021-04-05 | criteria provided, single submitter | clinical testing | The p.P776L variant (also known as c.2327C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 2327. The proline at codon 776 is replaced by leucine, an amino acid with similar properties. This variant was detected in a cardiomyopathy and arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This variant was also detected in a thoracic aortic aneurysm and dissection (TAAD) cohort; however, clinical details were limited (Hanania HL et al. Circ Genom Precis Med, 2019 12;12:e002626). This amino acid position is highly conserved in available vertebrate species. 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. |