Submissions for variant NM_005477.3(HCN4):c.2801G>A (p.Arg934His)

gnomAD frequency: 0.00003  dbSNP: rs369485237

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000180272	SCV000232672	uncertain significance	not provided	2014-11-04	criteria provided, single submitter	clinical testing
Invitae	RCV001240664	SCV001413632	uncertain significance	Brugada syndrome 8	2023-12-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 934 of the HCN4 protein (p.Arg934His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 198819). 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.
Ambry Genetics	RCV002433782	SCV002749772	uncertain significance	Cardiovascular phenotype	2022-04-04	criteria provided, single submitter	clinical testing	The p.R934H variant (also known as c.2801G>A), located in coding exon 8 of the HCN4 gene, results from a G to A substitution at nucleotide position 2801. The arginine at codon 934 is replaced by histidine, an amino acid with highly similar properties. A functional assay suggested this alteration has no impact on protein function (Jou CJ et al. Cell Physiol Biochem, 2017 Aug;42:2021-2029). This amino acid position is well conserved in available 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.
GeneDx	RCV000180272	SCV003927459	uncertain significance	not provided	2023-05-15	criteria provided, single submitter	clinical testing	Has not been previously published in association with HCN4-related disease as pathogenic or benign to our knowledge; Using this variant as a control, functional studies indicate that it does not differ significantly from wildtype (Jou et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28803248)
Clinical Genetics, Academic Medical Center	RCV000180272	SCV001923784	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000180272	SCV001963146	uncertain significance	not provided		no assertion criteria provided	clinical testing