Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001218769 | SCV001390669 | uncertain significance | Brugada syndrome 8 | 2023-09-25 | criteria provided, single submitter | clinical testing | 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. 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 expected to disrupt HCN4 protein function. ClinVar contains an entry for this variant (Variation ID: 947654). This missense change has been observed in individual(s) with left ventricular noncompaction (PMID: 30471092, 34088380). This variant is present in population databases (rs760413254, gnomAD 0.003%). This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 468 of the HCN4 protein (p.Ala468Val). |
Ambry Genetics | RCV002393520 | SCV002702446 | uncertain significance | Cardiovascular phenotype | 2022-03-08 | criteria provided, single submitter | clinical testing | The p.A468V variant (also known as c.1403C>T), located in coding exon 4 of the HCN4 gene, results from a C to T substitution at nucleotide position 1403. The alanine at codon 468 is replaced by valine, an amino acid with similar properties. This alteration has been reported in a sudden cardiac death cohort, as well as a left ventricular non-compaction (LVNC) cohort (Hertz CL et al. Int J Legal Med, 2016 Jan;130:91-102; Richard P et al. Clin Genet, 2019 03;95:356-367). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |