ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.3382G>A (p.Gly1128Ser) (rs779132775)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000622158 SCV000736215 uncertain significance Cardiovascular phenotype 2016-01-14 criteria provided, single submitter clinical testing The p.G1128S variant (also known as c.3382G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 3382. The glycine at codon 1128 is replaced by serine, an amino acid with similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6367 samples (12734 alleles) with coverage at this position. This amino acid position is highly conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on available evidence to date, the clinical significance of this variant remains unclear.
GeneDx RCV000658270 SCV000780041 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HCN4 gene. The G1128S variant has not been published as pathogenic or been reported as benign to our knowledge. The G1128S variant is not observed in large population cohorts (Lek et al., 2016). However, it has been observed in at least four alleles from presumably healthy individuals referred for genetic testing at GeneDx. The G1128S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Nevertheless, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.
Invitae RCV001066403 SCV001231410 uncertain significance Brugada syndrome 8 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 1128 of the HCN4 protein (p.Gly1128Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 518776). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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.