Submissions for variant NM_005477.3(HCN4):c.1132C>T (p.Arg378Cys)

gnomAD frequency: 0.00001  dbSNP: rs758468167

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170938	SCV000223498	uncertain significance	not provided	2024-12-12	criteria provided, single submitter	clinical testing	Identified in a patient with sick sinus syndrome (SSS) in published literature; the variant was also identified in this patient's mother and brother who both had sinus bradycardia (PMID: 30196304); Identified in an individual with noncompaction cardiomyopathy (PMID: 30847666); A published functional study suggests slowed activation kinetics and reduced surface expression (PMID: 30196304); 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: 30196304, 30847666)
Ambry Genetics	RCV000619663	SCV000737997	uncertain significance	Cardiovascular phenotype	2023-06-14	criteria provided, single submitter	clinical testing	The p.R378C variant (also known as c.1132C>T), located in coding exon 2 of the HCN4 gene, results from a C to T substitution at nucleotide position 1132. The arginine at codon 378 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been detected in a proband with childhood onset sick sinus syndrome and in two relatives with bradycardia (Möller M et al. Cell Physiol Biochem. 2018 Sep;49(3):1197-1207). This variant has also been detected in an individual who underwent genetic testing for suspicion of noncompaction cardiomyopathy; however, details were limited (van Lint FHM et al. Neth Heart J. 2019 Jun;27(6):304-309). In vitro suggest this variant may impact channel function and protein cell-surface expression; however, additional evidence is needed to confirm these findings (Möller M et al. Cell Physiol Biochem. 2018 Sep;49(3):1197-1207). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001051690	SCV001215858	uncertain significance	Brugada syndrome 8	2022-04-11	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 378 of the HCN4 protein (p.Arg378Cys). This variant is present in population databases (rs758468167, gnomAD 0.01%). This missense change has been observed in individual(s) with sick sinus syndrome (PMID: 30196304). ClinVar contains an entry for this variant (Variation ID: 190779). 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. Experimental studies have shown that this missense change affects HCN4 function (PMID: 30196304). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000170938	SCV002563267	likely pathogenic	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478538	SCV002785975	uncertain significance	Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18	2021-08-26	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000170938	SCV005198432	uncertain significance	not provided	2023-01-05	criteria provided, single submitter	clinical testing
Clinical Genetics, Academic Medical Center	RCV000170938	SCV001925478	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000170938	SCV001957556	uncertain significance	not provided		no assertion criteria provided	clinical testing