Table 4.
CLDN16 disease-causing variants [32].
| Missense/Nonsense Mutations | ||||||
|---|---|---|---|---|---|---|
| Ref. | Nucleotide Change | Amino Acid Change | Protein Change | Variant Class | Exon | Domain |
| [84] | c.114C>A | Cys38Term | p.C38 * | DM a | 1 | N term |
| [78] | c.211A>G | Met71Val | p.M71V | DM | 1 | N term |
| [26] | c.212T>G | Met71Arg | p.M71R | DM | 1 | N term |
| [49] | c.212T>C | Met71Thr | p.M71T | DM | 1 | N term |
| [50] | c.239G>A | Cys80Tyr | p.C80Y | DM | 1 | TM1 |
| [49] | c.263G>A | Gly88Glu | p.G88E | DM | 1 | TM1 |
| [85] | c.290A>G | Asp97Gly | p.D97G | DM | 1 | ECS1 |
| [53] | c.295T>G | Trp99Gly | p.W99G | DM | 1 | ECS1 |
| [49,52] | c.330C>G | Ser110Arg b | p.S110R | DM | 2 | ECS1 |
| [49,86] | c.341G>A | Arg114Gln | p.R114Q | DM | 2 | ECS1 |
| [60] | c.340C>T | Arg114Term | p.R114 * | DM | 2 | ECS1 |
| [56] | c.346C>G | Leu116Val | p.L116V | DM | 2 | ECS1 |
| [45,66] | c.350G>A | Trp117Term | p.W117 * | DM | 2 | ECS1 |
| [87] | c.354G>A | Trp118Term | p.W118 * | DM | 2 | ECS1 |
| [52,88] | c.358T>C | Cys120Arg | p.C120R | DM | 2 | ECS1 |
| [49] | c.385C>T | Arg129Cys | p.R129C | DM | 2 | ECS1 |
| [50,54,64,71,86] | c.416C>T | Ala139Val | p.A139V | DM | 2 | ECS1 |
| [45,49,66,86] | c.421C>G | His141Asp | p.H141D | DM | 2 | ECS1 |
| [45,46,47,52,66,86] | c.434T>C | Leu145Pro | p.L145P | DM | 3 | ECS1 |
| [86,89] | c.446G>A | Arg149Gln | p.R149Q | DM | 3 | ECS1 |
| [45,46,86] | c.446G>T | Arg149Leu | p.R149L | DM | 3 | ECS1 |
| [26,50] | c.445C>T | Arg149Term | p.R149 * | DM | 3 | ECS1 |
| [45,46,47,49,52,66,86,88] | c.453G>T | Leu151Phe | p.L151F | DM | 3 | ECS1or TM2? |
| [45,49,66,86] | c.452T>G | Leu151Trp | p.L151W | DM | 3 | ECS1or TM2? |
| [50,54,71,86] | c.485G>T | Gly162Val | p.G162V | DM | 3 | TM2 |
| [26,46] | c.500T>C | Leu167Pro | p.L167P | DM | 3 | TM2 |
| [90] | c.539C>T | Pro180Leu | p.P180L | DM | 3 | ICL |
| [50,87,91] | c.547A>G | Lys183Glu | p.K183E | DM | 3 | ICL |
| [26,46,47,86] | c.571G>A | Gly191Arg | p.G191R | DM | 3 | TM3 |
| [65] | c.592G>C | Gly198Arg | p.G198R | DM | 3 | TM3 |
| [45,86] | c.593G>C | Gly198Ala | p.G198A | DM | 4 | TM3 |
| [26,46,66,86] | c.593G>A | Gly198Asp | p.G198D | DM | 4 | TM3 |
| [63] | c.602G>A | Gly201Glu | p.G201E | DM | 4 | TM3 |
| [92] | c.620G>A | Trp207Term | p.W207 * | DM | 4 | ECS2 |
| [45,46,47,49] | c.625G>A | Ala209Thr | p.A209T | DM | 4 | ECS2 |
| [49,59,89] | c.646C>T | Arg216Cys | p.R216C | DM | 4 | ECS2 |
| [55] | c.647G>A | Arg216His | p.R216H | DM | 4 | ECS2 |
| [49,93] | c.679G>C | Gly227Arg | p.G227R | DM | 4 | ECS2 |
| [26,46,47,94] | c.695T>G | Phe232Cys | p.F232C | DM | 4 | ECS2 |
| [50] | c.697G>C | Gly233Arg | p.G233R | DM | 4 | ECS2 |
| [26,46] | c.698G>A | Gly233Asp | p.G233D | DM | 4 | ECS2 |
| [61] | c.697G>T | Gly233Cys | p.G233C | DM | 4 | ECS2 |
| [52] | c.702G>T | Trp234Cys | p.W234C | DM | 4 | ECS2 |
| [26] | c.704C>T | Ser235Phe | p.S235F | DM | 4 | ECS2 |
| [45,46] | c.703T>C | Ser235Pro | p.S235P | DM | 4 | ECS2 |
| [77] | c.704C>A | Ser235Tyr | p.S235Y | DM | 4 | ECS2 |
| [49,95] | c.710G>A | Trp237Term | p.W237 * | DM | 4 | ECS2 |
| [26,45,46,52,66,71,87] | c.715G>A | Gly239Arg | p.G239R | DM | 4 | ECL2 or TM4? |
| [52] | c.734G>A | Gly245Asp | p.G245D | DM | 4 | TM4 |
| [82] | c.823A>T c | Lys275Term | p.K275 * | DM | 5 | C term |
| [81] | c.831T>G d | Tyr277Term | p.Y277 * | DM | 5 | C term |
| [52] | c.864C>G | Tyr288Term | p.Y288 * | DM | 5 | C term |
| [96] | c.908C>G e | Thr303Arg | p.T303R | DM | 5 | C term |
| Splicing Mutations | ||||||
| Ref. | Nucleotide Change | Splicing Mutation | Variant Class | |||
| [45] | c.325-5T>G | IVS1 as T-G -5 | DM | |||
| [60] | c.427+5G>A | IVS2 ds G-A +5 | DM | |||
| [26] | c.593-2A>G | IVS3 as A-G -2 | DM | |||
| [49,59] | c.784+1G>T | IVS4 ds G-T +1 | DM | |||
| [45] | c.785-14T>G | IVS4 as T-G -14 | DM | |||
| Small Deletions | ||||||
| Nucleotide Change | Protein Change | Variant Class | Exon | Domain | ||
| [97] | c.166delG f | p.(Ala56Leufs*16) | DM? | 1 | N term | |
| [49] | c.235delG g | p.(Ala79fsX90) | 1 | TM1 | ||
| [45] | c.368delA | p.(Asn123Metfs*21) | DM | 2 | ECS1 | |
| [49] | c.408_410delCAT | p.(Ile137del) | DM | 2 | ECS1 | |
| [61] | c.800delG | p.(Arg267Lysfs*7) | DM | 5 | C term | |
| Small Insertions | ||||||
| Nucleotide Change | Protein Change | Variant Class | Exon | Domain | ||
| [74] | c.324+3_324+4insT | Not available | DM | intron 1 | ||
| [71] | c.545_548dupTTAA | p.(Lys183Asnfs*2) | DM | 3 | ICL | |
| Small Indels | ||||||
| Nucleotide Change | Protein Change | Variant Class | Exon | Domain | ||
| [45,66] | c.165_166delGGinsC | p.(Arg55Serfs*17) | R | 1 | N term | |
| [45,46] | c.646_647delCGinsAC | p.(Arg216Thr) | DM | 4 | ECS2 | |
| Gross Deletions | ||||||
| DNA Level | Description | Variant Class | Exon | Domain | ||
| [71,98] | g.DNA | Ex. 2-5 | DM | 2-5 | ||
| Complex Mutations | ||||||
| Description | Variant Class | Exon | Domain | |||
| [62] | c.574_589delins23bp | p.(A192Yfs∗ 25) | DM | 3 | TM3 | |
Variant class is described according the Human Gene Mutation Database [37] DM: Disease-causing mutations; DM?: probable/possible pathological mutation; «Retired records (R)», a variant that has been removed from HGMD if found to have been erroneously included ab initio or if the variant has been subject to retraction/correction in the literature resulting in the record becoming obsolete, merged or otherwise invalid. Domains are described according to authors and [99]. C Term, COOH terminus; TM, transmembrane domain; ECS1, first extracellular segment; ICL, intracellular loop; ECS2, second extracellular segment; N Term, NH2 terminus. a: the «significance» described by Trujillano was “likely pathogenic according to ACMG guidelines.” They categorized patients’ phenotypes according to the Human Phenotype Ontology nomenclature based on the clinical data and preceding workup provided by the referring physician. The phenotype described was: psychosis, seizures, muscle weakness, respiratory failure, reduced dihydropyrimidine dehydrogenase activity, decreased body weight, reduced consciousness/confusion, lower limb muscle weakness; b: reported as p.S110R 329AGC>AGG; c: reported as p.L203*, c.822A>T; d: reported as p.Y207*, c.620T>G; e: reported as p.T233R, c.697C>G; f: reported as c.164delG; g: reported as 236delG, p.A80fsX91,; * indicates that the predicted consequence is a termination codon.