ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3487C>A (p.Pro1163Thr) (rs779811451)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
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 2020-07-15 criteria provided, single submitter clinical testing This sequence change replaces proline with threonine at codon 1163 of the HCN4 protein (p.Pro1163Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. This variant is present in population databases (rs779811451, ExAC 0.03%). This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 519345). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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.