Submissions for variant NM_005477.3(HCN4):c.1444G>A (p.Gly482Arg)

dbSNP: rs794727637

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000178241	SCV000230285	likely pathogenic	not provided	2016-06-09	criteria provided, single submitter	clinical testing
Invitae	RCV000647252	SCV000769041	pathogenic	Brugada syndrome 8	2023-11-19	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 482 of the HCN4 protein (p.Gly482Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with sinus node dysfunction and left ventricular non compaction (PMID: 25145517, 25145518, 26206080, 27173043). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197253). 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 with a positive predictive value of 80%. Experimental studies have shown that this missense change affects HCN4 function (PMID: 25145518). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000178241	SCV001791508	pathogenic	not provided	2022-10-30	criteria provided, single submitter	clinical testing	Observed in multiple unrelated patients in association with bradycardia, LVNC, sinus node dysfunction, and/or non-compaction cardiomyopathy referred for genetic testing at GeneDx and in the published literature (Millat et al., 2015; Schweizer et al., 2014; Ishikawa et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies showed that p.(G482R) mutant subunits were non-functional and showed a dominant-negative effect on the channel current (Milano et al., 2014; Schweizer et al., 2014); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25145519, 25642760, 27173043, 26206080, 28104484, 26688388, 30471092, 32577394, 34088380, 25145517, 25145518, 35328031, 33185997)
Ambry Genetics	RCV002390435	SCV002701522	pathogenic	Cardiovascular phenotype	2021-08-27	criteria provided, single submitter	clinical testing	The p.G482R pathogenic mutation (also known as c.1444G>A), located in coding exon 4 of the HCN4 gene, results from a G to A substitution at nucleotide position 1444. The glycine at codon 482 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with sinus bradycardia and left ventricular non-compaction (LVNC) (Schweizer PA et al. J Am Coll Cardiol, 2014 Aug;64:757-67; Millat G et al. Eur J Med Genet, 2015 Sep;58:439-42; Chanavat V et al. Clin Chim Acta, 2016 Jan;453:80-5; Ishikawa T et al. Heart Rhythm, 2017 05;14:717-724; Hanania HL et al. Circ Genom Precis Med, 2019 12;12:e002626; Richard P et al. Clin Genet, 2019 03;95:356-367; Wacker-Gussmann A et al. HeartRhythm Case Rep, 2020 Jun;6:352-356). In vitro studies demonstrated that this alteration may impact protein function (Schweizer PA et al. J Am Coll Cardiol, 2014 Aug;64:757-67). Further, a different alteration located at the same position, resulting in the same protein change, c.1444G>C (p.G428R), has been reported in affected individuals and was found to segregate with disease in a family (Milano A et al. J Am Coll Cardiol, 2014 Aug;64:745-56). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.