Table 5.
Predicted pathogenicity of somatic CACNA1D variants reported in APAs and APCCs
| Position | Variant | Reference | Gating change | Times reported | Reported in gnomAD (#) | Pathogenicity |
|---|---|---|---|---|---|---|
| E124 | E124K | [60] | - | 1 | - | Likely pathogenic |
| Other gnomAD entries at this position: |
E124Q (1×) E124D (3×) |
|||||
| L248 | L248F | [60] | - | 1 | - | Likely pathogenic |
| V259 | V259A | [75] | - | 1× (germline) | - | |
| V259D | [3, 17] | Type-2 [3] | 3 | - | Pathogenic | |
| V259G | [60] | - | 1 | - | Pathogenic | |
| L272 | L272R | [60] | 1 | - | Likely pathogenic | |
| V309 | V309A | [56] | - | 1 | - | Likely pathogenic |
| Other gnomAD entries at this position: |
V309I (84×; HOM: 1×) |
|||||
| G323 | G323R | [60] | - | 1 | - | Likely pathogenic |
| V401 | V401L | [65] | Type-2 [65] | 1× (germline) | - | |
| V401L | [1, 56, 60] | Type-2 [65] |
4 (exon 8a) |
- | Pathogenic | |
| G403 | G403D | [18, 72] | Type-1 [72] | 2× (germline) | - | |
| G403R | [1, 3, 17, 34, 56, 57, 59, 60, 72, 73, 95, 100] | Type-1 [3,72] |
54 (exon 8a: 32; 8b: 12; ns: 10) |
- | Pathogenic | |
| Other gnomAD entries at this position: |
G403dup (2×) loss of function, exon 8b [4] |
|||||
| S410 | S410L | [59, 60] | - | 2 | - | Pathogenic |
| E412 | E412D | [95] | - | 1 | - | Likely pathogenic |
| G457 | G457R | [59] | - | 1 | 1× | Uncertain |
| Other gnomAD entries at this position: | G457del (2×) | |||||
| R510 (R530) | R510X | [59] | - | 1 | - | Likely benign |
| Other gnomAD entries at this position: | R510Q (2×) | |||||
| P548 (P568) | P548L | [59] | - | 1 | - | Likely pathogenic |
| L613 (L633) | L613Q | [57] | - | 1 | - | Likely pathogenic |
| R619 (R639) | R619P | [56] | - | 1 | - | Likely pathogenic |
| R619W | [57] | - | 1 | 1× | Uncertain | |
| S652 (S672) | S652L | [15] | 2× (germline)* | - | ||
| S652L | [17, 56, 60, 95] | Type-2 [26] | 5 | - | Pathogenic | |
| Other gnomAD entries at this position: | S652W (3×)—no gating change [26] | |||||
| L653 (L673) | L653P | [60] | - | 1 | - | Likely pathogenic |
| L655 (L675) | L655P | [17] | - | 1 | - | Likely pathogenic |
| Other gnomAD entries at this position: | L655F (1×) | |||||
| S724 (S744) | S724L | [60] | - | 1 | - | Likely pathogenic |
| V728 (V748) | V728I | [90] | - | 1 | 115× | Likely benign |
| Y741 (Y761) | Y741C | [17] | - | 1 | - | Likely pathogenic |
| F747 (F767) | F747C | [55, 56, 59] | - | 3 | - | Pathogenic |
| F747L | [1, 3, 17, 56, 57, 59, 60, 87, 95] | Type-2 [66] | 21 | - | Pathogenic | |
| F747V | [17, 55, 57, 59, 60, 73, 95] | - | 18 | - | Pathogenic | |
| L748 (L768) | L748S | [60] | - | 1 | - | Likely pathogenic |
| I750 (I770) | I750M | [72] | Type-2 [72] | 1× (germline) | - | |
| I750M | [3, 17, 34, 56, 72, 73, 95] | Type-2 [72,3] | 11 | - | Pathogenic | |
| I750F | [17, 56] | - | 2 | - | Pathogenic | |
| V752 (V772) | V752G | [95] | - | 1 | - | Likely pathogenic |
|
755-757del (775-777del) |
Deletion of “LAD’ | [60] | - | 1 | - | Likely pathogenic |
| Other gnomAD entries at this position: | A756T (1×) | |||||
| S969 (S989) | S969L | [60] | - | 1 | - | Likely pathogenic |
| V979 (V999) | V979D | [17] | - | 1 | - | Likely pathogenic |
| Other gnomAD entries at this position: | V979I (1×) | |||||
| K981 (K1001) | K981N | [17] | - | 1 | - | Likely pathogenic |
| R990 (R1010) | R990G | [56] | - | 1 | - | Pathogenic |
| R990H | [3, 59, 60, 87, 95] | Type-4 [52] | 9 | - | Pathogenic | |
| R993 (R1013) | R993T | [56] | - | 3 | - | Pathogenic |
| R993S | [95] | - | 1 | - | Pathogenic | |
| A998 (A1018) | A998I | [17] | - | 3 | - | Pathogenic |
| A998V | [17, 56, 59, 60, 95] | - | 9 | - | Pathogenic | |
| C1007 (C1027) | C1007R | [56] | - | 1 | - | Likely pathogenic |
| A1011 (A1031) | A1011T | [60] | - | 1 | - | Likely pathogenic |
| I1015 (I1035) | I1015S | [56] | - | 1 | - | Pathogenic |
| I1015V | [60, 95] | - | 2 | - | Pathogenic | |
| F1147 (F1167) | F1147C | [59] | - | 1 | - | Pathogenic |
| F1147L | [59, 60] | - | 2 | - | Pathogenic | |
| V1151 (V1171) | V1151F | [17, 56] | - | 3 | - | Pathogenic |
| I1152 (I1172) | I1152N | [17] | - | 1 | - | Likely pathogenic |
| V1153 (V1173) | V1153G | [87] | Type-2 [87] | 1 | - | Pathogenic |
| Other gnomAD entries at this position: | V1153I (3×) | |||||
| R1183 (R1203) | R1183H | [60] | - | 1 | - | Likely pathogenic |
| Other gnomAD entries at this position: | R1183C (2×) | |||||
| F1248 (F1268) | F1248L | [59, 60] | - | 4 | - | Pathogenic |
| D1273 (D1293) | D1273N | [60] | - | 1 | - | Likely pathogenic |
| P1336 (P1371) | P1336R | [3, 17, 59] | Type-3 [3] | 4 | - | Pathogenic |
| V1338 (V1373) | V1338M | [1, 17, 57, 59, 60, 73] | - | 13 | - | Pathogenic |
| I1352 (I1387) | I1352T | [59] | - | 1 | - | Likely pathogenic |
| M1354 (M1389) | M1354I | [3, 17] | No gating change [66] | 2 | - | Pathogenic/uncertain# |
| P1499 (P1534) | P1499L | [59] | - | 1 | - | Likely pathogenic |
| T1835 (T1879) | T1835I | [60] | - | 1 | - | Likely pathogenic |
| W1836 (W1880) | W1836X | [59] | - | 1 | - | Likely pathogenic |
Criteria for the classification of the pathogenicity are given in Table 4. The reference CACNA1D sequence EU_363339 contains exon 8a but not exons 11, 32, 44 (gnomAD reference sequence NM_000720 contains exons 8b, 11, 32, and 44). If the residue position differs between the two sequences, the respective NM_000720 residue is given in parenthesis. HOM, homozygous; “X” indicates a STOP. *Monozygotic twins. ns, not specified; “-” indicates not measured (gating change) or not reported in gnomAD. #M1354I fulfills the here described criteria of a pathogenic variant, but no typical gating changes have been observed in functional studies [66]. The W1836X variant lacks the distal C-terminal regulatory domain (DCRD), which disrupts an automodulatory interaction with the proximal C-terminus (PCRD), thereby interfering with channel gating (enhanced Ca2+-dependent inactivation and voltage sensitivity). The premature stop in the R510X variant likely results in a truncated, non-functional channel (loss of function)