Recent genome-wide association studies suggested that SCN10A common variants modulate PR and QRS duration. SCN10A encodes the sodium channel NaV1.8, initially cloned from dorsal root ganglion (DRG) neurons but more recently identified in the heart. We identified 3 rare variants (417delK, A1886V, R814H) that associated with lone atrial fibrillation and slow ventricular rates. We hypothesized that these mutations affect NaV1.8 biophysics, thus providing a mechanism for the associated disease. Here we functionally characterized these variants. Site-directed mutagenesis was used to generate the mutants and whole-cell patch-clamp experiments were performed to study the biophysics of the variants transiently expressed in ND7/23 cells. Whole-cell currents were recorded 48 hours after transfection at 37°C. Compared with wild-type (WT) channel, A1886V displayed a larger peak I Na (103 ± 16.6 pA/pF vs 43 ± 4.8 pA/pF, P <.05, n = 10 cells/group), and increased late sodium current (I Na-L ) (13.9 ± 1.9 % vs 6.1 ± 0.9 %, P <.01). Similarly, R814H showed a significant larger peak I Na (187.1 ± 22.6 pA/pF vs 43 ± 4.8 pA/pF, P <.01) and increased I Na-L (13.3 ± 1.1 % vs 6.1 ± 0.9 %, P <.01). In contrast, 417delK showed a significant reduction in peak I Na (7.5 ± 1.4 pA/pF vs 43 ± 4.8 pA/pF, P <.01) but increased I Na-L (17.5 ± 4.1 % vs 6.1 ± 0.9 %, P <.05). Because incubation at lower temperatures can rescue some ion channels that fail to reach the cell surface, 417delK(+) ND cells were incubated at 28°C the last 24 hours. This maneuver tripled 417delK current density (21 ± 3.1 pA/pF vs 7.5 ± 1.4 pA/pF at 37°C, P <.01) with no effect on WT current density (Table). All 3 variants studied showed significantly increased I Na-L , which supports the idea that they are causative for the variable cardiac conduction. Partially rescued 417delK I Na after incubation at 28°C might be explained by rescue of a trafficking defect that prevented delivery of the channel to plasma membrane. Additional parameters for SCN10A WT and rare variants Additional parameters for SCN10A WT and rare variants WT (37°C) WT (28°C) 417delK (37°C) 417delK (28°C) A1886V (37°C) R814H (37°C) Peak I Na (pA/pF) –43 ± 4.8 –41 ± 3 –7.5 ± 1.4 (P <.01 vs WT 37°C) –21 ± 3.1 (P <.01 vs 417delK 37°C) –103 ± 16.6 (P <.05 vs WT 37°C) –187.1 ± 22.6 (P <.01 vs WT 37°C) Voltage-to-peak I Na (mV) +3.6 ± 1.4 +5 ± 3.4 +6.2 ± 1.8 +3.8 ± 1.4 +7.5 ± 1.6 +15.9 ± 1.2 (P <.01 vs WT 37°C) Late I Na (I Na-L ) (% I Na ) 6.1 ± 0.9 6 ± 1 17.5 ± 4.1 (P <.05 vs WT 37°C) 8.7 ± 0.4 (P <.05 vs WT 28°C) 13.9 ± 1.9 (P <.01 vs WT 37°C) 13.3 ± 1.1 (P <.01 vs WT 37°C) τ fast (ms) 2.8 ± 0.1 3 ± 0.2 2 ± 0.2 (P <.05 vs WT 37°C) 2.3 ± 0.2 5 ± 0.5 (P <.05 vs WT 37°C) 3 ± 0.2 τ slow (ms) 22.4 ± 2.3 20 ± 1.7 11.5 ± 2.1 (P <.05 vs WT 37°C) 17.9 ± 2.7 32.2 ± 3.9 18.1 ± 1.7 V 1/2 activation (mV) –8 ± 1 –7 ± 1.6 — 9.1 ± 1.1 –16 ± 1.9 –14 ± 1.1 K activation (mV) 5.3 ± 0.3 5.6 ± 0.5 — 6.1 ± 0.4 5.8 ± 0.4 6.3 ± 0.4 V 1/2 inactivation (mV) –79.9 ± 2.4 –74.9 ± 4 — –78.6 ± 2.1 –79.4 ± 4 –84.7 ± 1.4 K inactivation (mV) 11.7 ± 1.5 12 ± 2.1 — 13 ± 1 16.4 ± 1.8 14 ± 1.7