Potentially pathogenic SCN10A variants identified in patients with pure small fibre neuropathy at Maastricht UMC+ (n=1139 patients)
| SCN10A variants, Chr3, GRCh37,NM_006514.2 | Number of patients | Classification based on predictive algorithms22* | Location in SCN10A | MAF ExAC (%) | Cell electrophysiology | Cosegregation | Classification according to Waxman recommendations23 | Reference | |
| c.position | p.position | ||||||||
| c.41G>T | p.(Arg14Leu) | 4 | 3 | N-terminus | 0.2 (234/121 350) | N/A | 1 family tested, segregation inconclusive† | VUS | – |
| c.626G>A | p.(Arg209His) | 1 | 3 | Loop DI/S3-DI/S4 | 0.003 (4/121 360) | N/A | N/A | VUS | – |
| c.1141A>G | p.(Ile381Val) | 1 | 4 | DI/S6 | 0.05 (63/121 384) | N/A | N/A | Possibly pathogenic variant | – |
| c.1667A>T | p.(Gln556Leu) | 1 | 3 | Linker DI/S6-DII/S1 | – | N/A | N/A | VUS | – |
| c.1879T>C | p.(Ser627Pro) | 1 | 3 | Linker DI/S6-DII/S1 | 0.003 (3/120 550) | N/A | N/A | VUS | – |
| c.2221C>G | p.(Leu741Val) | 1 | 3 | DII/S3 | 0.01 (18/120 924) | N/A | N/A | VUS | – |
| c.2972C>T | p.(Pro991Leu) | 4 | 3 | Linker DII/S6-DIII/S1 | 0.09 (108/121082) | N/A | 2 family tested, segregation with disease (n=1), segregation inconclusive (n=1)† | VUS | – |
| c.3482T>C | p.(Met1161Thr) | 1 | 4 | DIII/S1 | 0.02 (27/121 036) | N/A | N/A | Possibly pathogenic variant | – |
| c.3607C>T‡ | p.(Leu1203Phe) | 1 | 3 | DIII/S2 | – | N/A | N/A | VUS | – |
| c.3674T>C | p.(Ile1225Thr) | 1 | 3 | DIII/S3 | 0.06 (70/121 240) | N/A | 1 family tested, segregation with disease | Probably pathogenic variant | – |
| c.3766C>T | p.(Arg1256Trp) | 1 | 4 | DIII/S4 | 0.003 (3/121 100) | N/A | N/A | Probably pathogenic variant | – |
| c.3803G>A | p.(Arg1268Gln) | 4 | 3 | Loop DIII/S4-DIII/S5 | 0.2 (213/120 708) | N/A | N/A | VUS | – |
| c.3910G>A | p.(Ala1304Thr) | 1 | 4 | DIII/S5 | 0.004 (5/121 410) | Gain-of-function | N/A | Probably pathogenic variant | 12 |
| c.4139G>A | p.(Arg1380Gln) | 1 | 3 | Loop DIII/S5-DIII/S6 | 0.009 (10/110 106) | N/A | N/A | VUS | – |
| c.4378C>T | p.(Arg1460Trp) | 1 | 3 | Linker DIII/S6-DIV/S1 | 0.05 (58/121 296) | N/A | N/A | VUS | – |
| c.4562G>A | p.(Gly1521Asp) | 1 | 3 | DIV/S2 | – | N/A | N/A | VUS | – |
| c.4568G>Aठ| p.(Cys1523Tyr) | 9 | 4 | DIV/S2 | 0.1 (135/121 358) | DRG neuron hyperexcitability | N/A | Probably pathogenic variant | 12 |
| c.4724T>C | p.(Ile1575Thr) | 1 | 4 | DIV/S4 | – | N/A | N/A | VUS | – |
| c.4878G>A | p.(Met1626Ser) | 1 | 3 | DIV/S5 | 0.00008 (1/121 408) | N/A | N/A | VUS | – |
| c.4984G>A | p.(Gly1662Ser) | 3 | 4 | Loop DIV/S5-DIV/S6 | 0.2 (190/121 360) | Gain-of-function | N/A | Pathogenic variant | 35 |
| c.5116A>G | P.(Ile1706Val) | 1 | 4 | DIV/S6 | – | Gain-of-function | N/A | Probably pathogenic variant | 36 |
| c.5200G>A§ | p.(Glu1734Lys) | 1 | 3 | C-terminus | 0.02 (20/121 400) | N/A | N/A | VUS | – |
| c.5474T>C | p.(Met1825Thr) | 1 | 3 | C-terminus | – | N/A | N/A | VUS | – |
| c.5539C>T | p.(Arg1847Ter) | 1 | 3 | C-terminus | 0.003 (3/121 404) | N/A | N/A | VUS | – |
| c.5606G>A | p.(Arg1869His) | 1 | 3 | C-terminus | 0.004 (5/121 402) | N/A | N/A | VUS | – |
c. position, location cDNA; p. position, location in protein.
*2, unlikely to be pathogenic; 3, uncertain clinical significance; 4, likely to be pathogenic.
†Inconclusive, affected family members with minor complaints were negative for the variant (c.41G>T and c.2972C>T).
‡One patient was heterozygous for c.3607C>T and c.4568G>A variant.
§One patient was heterozygous for c.4568G>A and c.5200G>A variant
MAF ExAC, Minor Allele Frequency Exome Aggregation Consortium; N/A, not available; VUS, variants with uncertain clinical significance.