Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV000700797 | SCV000829568 | uncertain significance | Brugada syndrome 8 | 2023-10-25 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 127 of the HCN4 protein (p.Glu127Lys). This variant is not present in population databases (gnomAD no frequency). 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: 577931). 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. |
Ambry Genetics | RCV002352190 | SCV002622242 | uncertain significance | Cardiovascular phenotype | 2021-11-04 | criteria provided, single submitter | clinical testing | The p.E127K variant (also known as c.379G>A), located in coding exon 1 of the HCN4 gene, results from a G to A substitution at nucleotide position 379. The glutamic acid at codon 127 is replaced by lysine, an amino acid with similar properties. This alteration has been reported in an individual with familial thoracic aortic aneurysm, having an additional alteration in MYLK identified (Schweizer PA et al. J Am Coll Cardiol, 2017 03;69:1209-1210). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |