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

gnomAD frequency: 0.00001  dbSNP: rs794727637

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861463	SCV002230630	pathogenic	Brugada syndrome 8	2021-08-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects HCN4 function (PMID: 25145517, 25145518). 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. ClinVar contains an entry for this variant (Variation ID: 374859). This missense change has been observed in individual(s) with clinical features of HCN4-related conditions (PMID: 25145517, 25145518, 26206080, 26688388, 28104484, 30471092). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 482 of the HCN4 protein (p.Gly482Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine.
OMIM	RCV000415605	SCV000493945	pathogenic	Sick sinus syndrome 2, autosomal dominant	2014-08-26	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001729574	SCV001978102	pathogenic	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001729574	SCV001979867	pathogenic	not provided		no assertion criteria provided	clinical testing