Table 1.
Human KCNA1 mutations designated as “pathogenic” or “likely pathogenic” with heterogenous phenotypes.
| Mutation | Protein Domain | Clinical Diagnoses | Other Clinical Observations | Reference |
|---|---|---|---|---|
| R167M | S1 | EA1 | [8] | |
| A170S | S1 | EA1 | [9] | |
| V174F | S1 | EA1 | [10,11] | |
| I176R | S1 | EA1 | [12] | |
| I177N | S1 | EA1 | [13] | |
| F184C | S1 | EA1 + Seizures | [14] | |
| C185W | S1 | EA1 + Hyperthermia | Sleep a | [8,15,16] |
| T226A | S2 | EA1 | [12] | |
| T226M | S2 | EA1 | [17] | |
| T226K | S2 | Myokymia | [18] | |
| T226R | S2 | EA1 + Epilepsy | Respiratory b, Sleep c, DD | [19,20] |
| R239S | S2 | EA1 | [11] | |
| A242P | S2 | Neuromyotonia + Seizures | [8,21] | |
| P244H | S2–S3 IL | Myokymia | [21] | |
| F249C | S2–S3 IL | EA1 + Hyperthermia | [22] | |
| F249I | S2–S3 IL | EA1 | [11] | |
| FF>F250 | S2–S3 IL | EA1 | Respiratory d | [23,24] |
| N255D | S3 | Hypomagnesemia | [25,26] | |
| N255K | S3 | PKD | [27] | |
| I262T | S3 | EA1 | [28,29] | |
| I262M | S3 | EA1 | [30] | |
| E283K | S3–S4 EL | EA1 | [31] | |
| V299I | S4 | EA1 + PMC | [32] | |
| F303V | S4 | EA1 | [33] | |
| L305F | S4 | EA1 | [34] | |
| R307C | S4 | EA1 | [7] | |
| G311D | S4–S5 IL | EA1 | [35] | |
| G311S | S4–S5 IL | EA1 | [36] | |
| I314T | S4–S5 IL | EA1 | [19] | |
| L319R | S4–S5 IL | PKD + Seizures | [27] | |
| R324T | S5 | EA1 + Epilepsy | [37] | |
| E325D | S5 | EA1 | [38] | |
| L328V | S5 | Hypomagnesemia | [39] | |
| L329I | S5 | EA1 | [40] | |
| S342I | S5 | EA1 + Seizures | [28,41] | |
| V368L | S5–S6 pore loop |
EE | Severe ID | [42] |
| A395S | S6 | EA1 | * | |
| P403S | S6 (PVP) | EA1 + Epilepsy | Respiratory e, DD, Moderate ID | [43] |
| V404I | S6 (PVP) | EA1 | Mild ID | [12,21,44] |
| P405S | S6 (PVP) | EE | DD, Macrocephaly f | [43] |
| P405L | S6 (PVP) | EE | PDD g | [43,45] |
| I407M | S6 | EA1 | [8] | |
| V408A | S6 | EA1 | [11] | |
| V408L | S6 | EA1 + Seizures | Global DD | [46] |
| F414C | C Terminus | EA1 | [47] | |
| F414S | C Terminus | EA1 + Epilepsy | [16] | |
| R417stop | C Terminus | EA1 | [21] |
Human SNP mutations were identified using the NCBI ClinVar and dbSNP databases. The full list of KCNA1 mutations was filtered by the categories “Pathogenic” and “Likely Pathogenic.” The compiled list of human mutations was used as search criteria in PubMed to find clinical discussions of patients with these mutations and the functional research associated with them. Additional literature searches were also used to identify mutations not yet listed in the NCBI genetic databases. A compilation of “Benign”, “Likely Benign”, and “Uncertain Significance” mutations was also accomplished through the NCBI database ClinVar [48]. Abbreviations: IL, intracellular linker; EL, extracellular linker; PVP, proline-valine-proline motif; PKD, paroxysmal kinesigenic dyskinesia; EE, epileptic encephalopathy; PMC, paradoxical myotonic congenita; DD, developmental delay; ID, intellectual disability; PDD, pervasive developmental disorder. * published citation could not be found; ClinVar variation label NM_000217.3(KCNA1):c.1183G>T (p.Ala395Ser) and accession number VCV000431378.; a self-reported needing only 5–6 h of sleep per night and being very active during the night; b recurrent apneic episodes with cyanosis; c prolonged sleep latency, reduced sleep efficiency, obstructive sleep apnea, hypopnea, ~80% oxygen desaturation during sleep; d difficulty breathing during attacks and isolated episodes of an inability to inhale; e before age 2, very loud breathing at night; f head circumference in the 93rd percentile; g now also called autism spectrum disorder.