Table 2.
Missense variants found in the Czech cohort. Variants were evaluated by in silico tools (CADD, Polyphen, and SIFT). The Proof of Pathogenicity column provides information on which the variant evaluation is based. 'MP' indicates multiple published patients (including this study), while 'FP' signifies functional proof of variant impact with referenced articles containing such evidence. The Proof of pathogenicity column provides information on which the variant evaluation is based with “MP” indicating multiple published patients (including this study), and “FP” functional proof of variant impact. The resources are indicated in the References column, and articles containing functional proof are [33, 34, 57]$$$$$$$$$. The numbers of patients and probands of our cohort are given in corresponding columns. # indicates previously published probands/patients, and x in x# indicates the number of them. Two substitutions in the position c.550 were included in the splicing variants subset (Table 5) because their pathomechanism is primarily disruption of mRNA splicing
| Variant cDNA | Variant protein | CADD | Polyphen category | SIFT category | Proof of pathogenicity | ACMG evaluation | Number of probands | Number of patients | References |
|---|---|---|---|---|---|---|---|---|---|
| c.498C > A | p.Asn166Lys | 24 | Probably damaging | Damaging | MP | Pathogenic | 1 | 1 | [12, 29–32] |
| c.503C > A | p.Ala168Asp | 22.9 | Probably damaging | Damaging | MP, FP [33, 34] | Pathogenic | 1 | 3 | [30, 31, 33, 34] |
| c.506 T > C | p.Phe169Ser | 29 | Probably damaging | Damaging | MP | Pathogenic | 1 | 2 | [35, 36] |
| c.548 T > C | p.Leu183Pro | 32 | Probably damaging | Damaging | MP | Pathogenic | 1# | 1# | [17, 37, 38] |
| c.614G > A | p.Cys205Tyr | 24.3 | Benign | Damaging | MP | Pathogenic | 1 | 3 | [37, 39, 40] |
| c.629 T > C | p.Leu210Pro | 24.8 | Probably damaging | Damaging | MP | Pathogenic | 1# | 21# | [17, 38, 41] |
| c.706 T > G | p.Phe236Val | 24.8 | Probably damaging | Damaging | Likely pathogenic | 1# | 21# | [17] | |
| c.722G > C | p.Arg241Pro | 14.82 | Probably damaging | Tolerated | MP, FP [33] | Likely pathogenic | 1 | 2 | [33, 36] |
| c.743C > G | p.Pro248Arg | 23.2 | Probably damaging | Damaging | MP | Likely pathogenic | 1 | 3 | [36, 42] |
| c.793 T > G | p.Trp265Gly | 25.4 | Probably damaging | Damaging | Likely pathogenic | 1# | 31# | [17] | |
| c.1046 T > C | p.Leu349Pro | 26.8 | Probably damaging | Damaging | MP | Pathogenic | 1# | 21# | [17, 43] |
| c.1195C > T | p.Pro399Ser | 23.2 | Probably damaging | Damaging | MP | Pathogenic | 1 | 2 | [36, 38, 44, 45] |
| c.1202 T > A | p.Ile401Asn | 25.5 | Probably damaging | Damaging | MP | Likely pathogenic | 1# | 21# | [17, 46] |
| c.1322 T > A | p.Met441Lys | 25.1 | Probably damaging | Damaging | Likely pathogenic | 1# | 31# | [17] | |
| c.1346 T > C | p.Leu449Pro | 28.9 | Probably damaging | Damaging | MP | Pathogenic | 1 | 1 | [30, 47] |
| c.1361 T > G | p.Val454Gly | 28.2 | Probably damaging | Damaging | MP | Pathogenic | 41# | 81# | [17] |
| c.1396C > T | p.Arg466Cys | 25.3 | Probably damaging | Damaging | MP, FP [57] | Pathogenic | 52# | 155# | [30, 32, 34, 36, 38, 45, 48–60] |
| c.1397G > A | p.Arg466His | 23.4 | Benign | Damaging | MP, FP [57] | Pathogenic | 62# | 174# | [28, 30, 32, 39, 46, 48, 50, 52, 54, 57, 61–64] |