Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ce |
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. |
Gene |
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, |
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 |