Submissions for variant NM_005477.3(HCN4):c.520C>T (p.Pro174Ser)

gnomAD frequency: 0.00007  dbSNP: rs542532555

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000170946	SCV000223506	uncertain significance	not provided	2020-12-28	criteria provided, single submitter	clinical testing	Has been reported in one individual with sick sinus syndrome (Jou et al., 2017); Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 190787; Landrum et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies using zebrafish embryos suggest that this variant is disease-causing (Jou et al., 2017); additional studies are needed to validate the effect of this variant; This variant is associated with the following publications: (PMID: 28803248)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000467858	SCV000541565	uncertain significance	Brugada syndrome 8	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 174 of the HCN4 protein (p.Pro174Ser). This variant is present in population databases (rs542532555, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with HCN4-related conditions. ClinVar contains an entry for this variant (Variation ID: 190787). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Center for Human Genetics, University of Leuven	RCV000497368	SCV000579561	uncertain significance	Hypertrophic cardiomyopathy	2017-04-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002336402	SCV002640573	uncertain significance	Cardiovascular phenotype	2022-12-01	criteria provided, single submitter	clinical testing	The p.P174S variant (also known as c.520C>T), located in coding exon 1 of the HCN4 gene, results from a C to T substitution at nucleotide position 520. The proline at codon 174 is replaced by serine, an amino acid with similar properties. This variant has been detected in an individual reported to have sick sinus syndrome, bradycardia and resuscitated sudden cardiac death, and in an individual from an arrhythmia and cardiomyopathy cohort for whom clinical details were not provided (Jou CJ et al. Cell. Physiol. Biochem., 2017 Aug;42:2021-2029; Robyns T et al. Eur. J. Hum. Genet., 2017 12;25:1313-1323). In one in vivo study using a zebrafish model, this variant showed a lower degree of abnormal heart rate and pause rescue when compared to wild type (Jou CJ et al. Cell. Physiol. Biochem., 2017 Aug;42:2021-2029). This amino acid position is not well conserved in available vertebrate species, and serine is the reference amino acid in other 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.
Fulgent Genetics, Fulgent Genetics	RCV002485073	SCV002791324	uncertain significance	Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18	2021-09-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739551	SCV005348608	uncertain significance	HCN4-related disorder	2024-08-07	no assertion criteria provided	clinical testing	The HCN4 c.520C>T variant is predicted to result in the amino acid substitution p.Pro174Ser. This variant has been reported in individuals with hypertrophic cardiomyopathy or sick sinus syndrome (Jou et al. 2017. PubMed ID: 28803248; Robyns et al. 2017. PubMed ID: 29255176). In a zebrafish model, this variant was considered to be non-functional (Jou et al. 2017. PubMed ID: 28803248). This variant is reported in 0.018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.