Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001047439 | SCV001211400 | uncertain significance | Brugada syndrome 8 | 2022-05-17 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1077 of the HCN4 protein (p.Gly1077Ser). 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 atrial fibrillation, dilated cardiomyopathy, and/or left ventricular non-compaction (PMID: 24607718, 28254188, 33500567). ClinVar contains an entry for this variant (Variation ID: 844561). 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. Experimental studies have shown that this missense change does not substantially affect HCN4 function (PMID: 24607718). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 | RCV002320269 | SCV002610275 | uncertain significance | Cardiovascular phenotype | 2020-01-22 | criteria provided, single submitter | clinical testing | The p.G1077S variant (also known as c.3229G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 3229. The glycine at codon 1077 is replaced by serine, an amino acid with similar properties. This variant was detected in an early onset atrial fibrillation cohort; however, whole patch clamp studies showed no significant impact (Macri V et al. Heart Rhythm, 2014 Jun;11:1055-1062). 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. |
| Victorian Clinical Genetics Services, |
RCV002471015 | SCV002767897 | uncertain significance | Sick sinus syndrome 2, autosomal dominant | 2020-10-19 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as 3B-VUS. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with sick sinus syndrome 2 (MIM#163800). Gain of function has been reported to cause inappropriate sinus tachycardia, a type of sinus node dysfunction (PMID: 28182231). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported as a VUS for Brugada syndrome (ClinVar) and it has also been identified in an individual with atrial fibrillation in a study assessing susceptibility to the condition (PMID: 24607718). In addition, it has been reported in an individual with dilated cardiomyopathy who also harboured the VUS p.(Arg589Trp) in the RBM20 gene (PMID: 28254189). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1004 - This variant has moderate functional evidence supporting normal protein function. Patch clamp experiments showed no significant difference compared to wild-type (PMID: 24607718). However, patch clamp assays have been shown to be unreliable therefore, results from these studies are used with caution during variant classification. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |