Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000621136 | SCV000737769 | uncertain significance | Cardiovascular phenotype | 2016-10-26 | criteria provided, single submitter | clinical testing | The p.P1163T variant (also known as c.3487C>A), located in coding exon 8 of the HCN4 gene, results from a C to A substitution at nucleotide position 3487. The proline at codon 1163 is replaced by threonine, an amino acid with highly similar properties. This variant has not been reported in the literature to date; however, internal structural analysis suggests this variant is more disruptive than another alteration involving the same amino acid, p.P1163A (c.3487C>G). Based on data from ExAC, the A allele has an overall frequency of less than 0.01% (2/78728) total alleles studied (TCGA excluded). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Invitae | RCV001339711 | SCV001533475 | uncertain significance | Brugada syndrome 8 | 2023-10-30 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1163 of the HCN4 protein (p.Pro1163Thr). This variant is present in population databases (rs779811451, gnomAD 0.02%). 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: 519345). 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. |
Gene |
RCV002285374 | SCV002575589 | uncertain significance | not provided | 2022-09-19 | criteria provided, single submitter | clinical testing | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function |