Submissions for variant NM_005477.3(HCN4):c.1123C>T (p.Arg375Cys)

gnomAD frequency: 0.00002  dbSNP: rs755356387

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000693215	SCV000821075	pathogenic	Brugada syndrome 8	2023-11-18	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 375 of the HCN4 protein (p.Arg375Cys). This variant is present in population databases (rs755356387, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of HCN4-related condition (PMID: 26688388, 30471092, 30578647, 33008772). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 571947). 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 with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV002293473	SCV002586687	likely pathogenic	not provided	2023-07-10	criteria provided, single submitter	clinical testing	Reported in association with LVNC, sudden death, and sinus bradycardia (Chanavat et al., 2016; Alonso-Fernandez-Gatta et al., 2021; Cambon-Viala et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a decreased current compared to wild type (Alonso-Fernandez-Gatta et al., 2021); 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: 30578647, 34088380, 33008772, 26688388)
Ambry Genetics	RCV003163166	SCV003860343	likely pathogenic	Cardiovascular phenotype	2023-03-06	criteria provided, single submitter	clinical testing	The p.R375C variant (also known as c.1123C>T), located in coding exon 2 of the HCN4 gene, results from a C to T substitution at nucleotide position 1123. The arginine at codon 375 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been reported in individuals with left ventricular non-compaction (LVNC) and sinus bradycardia, segregating with disease in one family (Chanavat V et al. Clin Chim Acta, 2016 Jan;453:80-5; Richard P et al. Clin Genet, 2019 Mar;95:356-367; Alonso-Fernández-Gatta M et al. Rev Esp Cardiol (Engl Ed), 2021 Sep;74:781-789; Ambry internal data). In vitro studies showed this alteration may impact protein function (Alonso-Fernández-Gatta M et al. Rev Esp Cardiol (Engl Ed), 2021 Sep;74:781-789). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This missense alteration is located in a region that has a low rate of benign missense variation (Lek M et al. Nature. 2016 Aug 18;536(7616):285-91; DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth H.V. et al. 2009. Am.J.Hum.Genet. 84, 524-533 (DOI: dx.doi.org/10/1016/j.ajhg.2009.03.010)). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV002293473	SCV004226893	pathogenic	not provided	2023-02-07	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PM1, PS3_moderate, PS4_moderate