ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.1005G>A (p.Met335Ile) (rs758797709)

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
Invitae RCV000542848 SCV000648430 uncertain significance Brugada syndrome 8 2020-05-10 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 335 of the HCN4 protein (p.Met335Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is present in population databases (rs758797709, ExAC 0.01%). This variant has not been reported in the literature in individuals with HCN4-related disease. ClinVar contains an entry for this variant (Variation ID: 470643). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). 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 RCV000620654 SCV000737534 uncertain significance Cardiovascular phenotype 2019-02-14 criteria provided, single submitter clinical testing The p.M335I variant (also known as c.1005G>A), located in coding exon 2 of the HCN4 gene, results from a G to A substitution at nucleotide position 1005. The methionine at codon 335 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and isoleucine is the reference amino acid in other 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 variant remains unclear.

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.