| Variant (protein; genomic if available) | Variant class | Functional consequence | Protein location/domain | Reported phenotype(s) | Notes | Citation |
|---|---|---|---|---|---|---|
| p.R378C | Missense | Loss-of-function; leftward/negative shift in activation reported for SND-associated variants | Transmembrane/channel region (exact subdomain not specified in available evidence) | Sinus node dysfunction / sick sinus syndrome, bradycardia | Listed among HCN4 variants with clear SND association | (pqac-00000002, pqac-00000011) |
| p.G482R | Missense | Loss-of-function | Pore domain | Sinus node dysfunction / sick sinus syndrome, bradycardia | Pore-domain variant highlighted among pathogenic SND variants | (pqac-00000002, pqac-00000011) |
| p.V492F | Missense | Loss-of-function | S6 helix, highly conserved region | Sinus node dysfunction / sick sinus syndrome, bradycardia | Conserved S6 localization supports functional importance | (pqac-00000002, pqac-00000016) |
| p.R524Q | Missense | Gain-of-function; enhanced cAMP sensitivity | C-linker/CNBD-proximal region (exact domain not specified in available evidence) | Familial inappropriate sinus tachycardia; sinus node dysfunction spectrum | Not a classic bradycardic SSS allele, but relevant HCN4 SND-spectrum variant | (pqac-00000002, pqac-00000018) |
| p.R550H | Missense | Loss-of-function; dominant-negative pattern described for most SND alleles | C-terminal cytoplasmic region (exact domain not specified in available evidence) | Sinus node dysfunction / sick sinus syndrome, bradycardia | One of the recurrent heterozygous SND-associated HCN4 variants | (pqac-00000002, pqac-00000011) |
| p.695X | Truncating / nonsense | Loss-of-function | Truncation of C-terminal channel region | Sinus node dysfunction / sick sinus syndrome, bradycardia | Premature stop expected to impair channel function | (pqac-00000002, pqac-00000011) |
| p.V759I; c.2275G>A | Missense | No demonstrable abnormality in available functional assays; likely benign/insufficient alone | Distal C-terminal region, exon 8 | Symptomatic sinus bradycardia, chronotropic incompetence, sinus pauses in reported carrier | Initially considered likely pathogenic in a family-history context, but functional testing did not support causality | (pqac-00000003, pqac-00000004, pqac-00000012, pqac-00000015) |
| p.P883R | Missense | Gain-of-function; positive voltage shift and faster deactivation | Distal C-terminus | Sinus node dysfunction spectrum | Exceptional because most HCN4 SND variants are loss-of-function | (pqac-00000002, pqac-00000011) |
| p.E1193Q | Missense | Loss-of-function | Distal C-terminus | Sinus node dysfunction / sick sinus syndrome, bradycardia | Distal C-terminal SND-associated variant | (pqac-00000002, pqac-00000011) |
| HCN4 SND-associated variants overall | Mostly missense, occasional truncating | Predominantly heterozygous dominant-negative loss-of-function via negative activation shift, reduced membrane expression, decreased current density, altered cAMP sensitivity, or trafficking defects | Frequently transmembrane/pore/C-terminal regulatory regions | Sinus bradycardia, sinus pauses/arrest, chronotropic incompetence, atrial fibrillation susceptibility; sometimes noncompaction cardiomyopathy | Review identified 22 reported HCN4 SND variants, with 13 considered to have clear genotype-phenotype association | (pqac-00000001, pqac-00000008, pqac-00000010, pqac-00000011) |


*Table: This table summarizes key HCN4 variants discussed in the available evidence for Sick Sinus Syndrome 2 and related sinus node dysfunction phenotypes. It highlights variant class, inferred functional effect, domain context, and clinical manifestations to support genotype-phenotype interpretation.*