ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3293C>T (p.Ala1098Val)

gnomAD frequency: 0.00003  dbSNP: rs1064797200
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Center for Human Genetics Tuebingen RCV000487975 SCV000575012 uncertain significance not provided 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000556954 SCV000648460 uncertain significance Brugada syndrome 8 2023-12-01 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1098 of the HCN4 protein (p.Ala1098Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 28254189). ClinVar contains an entry for this variant (Variation ID: 425072). 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 RCV000487975 SCV002003485 uncertain significance not provided 2020-10-19 criteria provided, single submitter clinical testing Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar but additional evidence is not available (ClinVar Variant ID #425072; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function
Ambry Genetics RCV002455941 SCV002611962 uncertain significance Cardiovascular phenotype 2023-02-16 criteria provided, single submitter clinical testing The p.A1098V variant (also known as c.3293C>T), located in coding exon 8 of the HCN4 gene, results from a C to T substitution at nucleotide position 3293. The alanine at codon 1098 is replaced by valine, an amino acid with similar properties. This variant was reported in an individual with dilated cardiomyopathy with limited clinical details provided (Arbustini E et al. J. Am. Coll. Cardiol., 2017 Mar;69:1210-1211). This amino acid position is 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.
Fulgent Genetics, Fulgent Genetics RCV002489184 SCV002794138 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-10-11 criteria provided, single submitter clinical testing

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.