ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3487C>A (p.Pro1163Thr)

gnomAD frequency: 0.00001  dbSNP: rs779811451
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
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.
GeneDx 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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.