Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001246540 | SCV001419899 | likely pathogenic | Brugada syndrome 8 | 2023-04-26 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Gly480 amino acid residue in HCN4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17646576, 24569893). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt HCN4 protein function. ClinVar contains an entry for this variant (Variation ID: 970883). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 28855170, 33082984). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 480 of the HCN4 protein (p.Gly480Ser). |
| Ambry Genetics | RCV002393656 | SCV002702876 | pathogenic | Cardiovascular phenotype | 2021-10-28 | criteria provided, single submitter | clinical testing | The p.G480S pathogenic mutation (also known as c.1438G>A), located in coding exon 4 of the HCN4 gene, results from a G to A substitution at nucleotide position 1438. The glycine at codon 480 is replaced by serine, an amino acid with similar properties. This alteration has been detected in left ventricle noncompaction (LVNC) cohorts (Wang C et al. J Am Heart Assoc, 2017 Aug;6; Ross SB et al. Hum Genome Var, 2020 Oct;7:33; Hirono K et al. Circ Genom Precis Med, 2020 08;13:e002940). This variant co-segregated with HCN4-related disease in one family tested in our laboratory. A structural analysis has determined G480S disrupts a key residue in the HCN selectivity filter motif and is mildly disruptive to protein structure (Ambry internal data). In vitro functional studies of a different alteration at this site (G480R) also predict changes at this site are likely to impact protein trafficking and channel function (Nof E et al. Circulation, 2007 Jul;116:463-70). This amino acid position is highly conserved in available vertebrate species. This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Agnes Ginges Centre for Molecular Cardiology, |
RCV001254756 | SCV001430849 | uncertain significance | Left ventricular noncompaction cardiomyopathy | 2019-05-07 | no assertion criteria provided | research | This variant has been identified as part of our research program. Refer to the 'condition' field for the phenotype of the proband identified with this variant. For further information please feel free to contact us. |