Submissions for variant NM_005477.3(HCN4):c.2917G>A (p.Gly973Arg)

gnomAD frequency: 0.00006  dbSNP: rs200495478

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000691006	SCV000818744	uncertain significance	Brugada syndrome 8	2023-12-31	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 973 of the HCN4 protein (p.Gly973Arg). This variant is present in population databases (rs200495478, gnomAD 0.02%). This missense change has been observed in individual(s) with sudden unexpected death in epilepsy (PMID: 21615589). ClinVar contains an entry for this variant (Variation ID: 570199). 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 with a negative predictive value of 95%. 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.
Fulgent Genetics, Fulgent Genetics	RCV000763982	SCV000894933	uncertain significance	Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001118934	SCV001277255	uncertain significance	Sick sinus syndrome 2, autosomal dominant	2017-06-30	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000995391	SCV001770793	uncertain significance	not provided	2022-05-11	criteria provided, single submitter	clinical testing	Reported in an individual with sudden unexplained death (SUD) and a history of epilepsy (Tu et al., 2011; Goldman et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26749013, 30452770, 33013630, 31018519, 21615589)
Ambry Genetics	RCV002440448	SCV002745977	uncertain significance	Cardiovascular phenotype	2023-04-03	criteria provided, single submitter	clinical testing	The p.G973R variant (also known as c.2917G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 2917. The glycine at codon 973 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in one sudden unexplained death epilepsy case (Tu E et al. Brain Pathol, 2011 Nov;21:692-8). This variant was also detected in one individual from a cardiomyopathy/arrhythmia genetic testing cohort; however, clinical details were limited, and additional cardiac variants were detected (van Lint FHM et al. Neth Heart J, 2019 Jun;27:304-309). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004535719	SCV004120278	uncertain significance	HCN4-related disorder	2024-02-28	no assertion criteria provided	clinical testing	The HCN4 c.2917G>A variant is predicted to result in the amino acid substitution p.Gly973Arg. This variant was reported in a large cohort of individuals with sudden unexpected death in epilepsy (Tu et al. 2011. PubMed ID: 21615589) and also in a large cohort of individuals with suspected cardiac disease (van Lint et al. 2019. PubMed ID: 30847666, supplementary data). However, this variant is reported in 0.018% of alleles in individuals of European (Non-Finnish) descent in gnomAD, which may be too frequent to be a primary cause of autosomal dominant disease. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.