Table 2B.
Novel pathogenic sequence variations identified in IPN genes by next-generation sequencing
| Patient | Disease classification | Inheritance | Gene | Haplotype | cDNA change | Amino acid change | ACMG | ExAC | Mutation Taster |
Polyphen-2 | UMD-Predictor | PhyloP |
| 1 | CMT2 | AR | MFN2 GDAP1 | het | c.311G>A c.400delG | p.Arg104Gln p.Asp134Metfs13 | PP P | NA NA | D1 NA | 1 PD NA | 100 P NA | 5,37 HC NA |
| 5 | CMT1 | SPO | INF2 | het | c.311G>A | p.Cys104Tyr | PP | NA | D1 | NA | NA | 5,69 HC |
| 7 | CMT2 | AD | GAN | het | c.862C>G | p.Pro288Ala | PP | NA | D1 | 0,001 B | NA | 2,95 MC |
| 13 | HSAN | AD | SPTLC2 (HSPB3) | het | c.1304G>T (c.246_246delT) | p.Gly435Val (p.Glu83Lysfs*13) | PP VUS | NA 5*10–5 | D1 NA | 1 PD NA | 78 P NA | 6,18 HC NA |
| 14 | CMT1 | AR | SH3TC2 | comp.het | c.[224G>C]; [3377T>C] |
p.[Arg75Pro]; [Leu1126Pro] |
PP/PP | NA/NA | D1/D1 | 1 PD/0999 PD | 81 P/ 84 P | 3,43 MC 4,81 HC |
| 19 | CMT2 | AR | GAN | hoz | c.890C>T | p.Pro297Leu | PP | NA | D1 | 0,906 Possibdam | NA | 5,86 HC |
| 22 | CMT2 | AD | AARS | het | c.525C>G | p.Phe175Leu | PP | 1/121242 | D1 | 1 PD | 96 P | 2,22 MC |
| 24 | CMT2 | AR | DARS2 | comp.het | c.[74_74delT(;)713C>T] | p.[Ile25fs*38(;) Ser238Phe] |
P/VUS | 2/ 121358/NA |
D1/NA | 0,959 PD/NA | 93 P/ NA | 0,85 WC NA |
| 26 | CMT2 | SPO | MFN2 | het | c.1127T>G | p.Met376Arg | PP | NA | D1 | 0,984 PD | 96 P | 4,48 HC |
| 29 | CMT2 | AD | LRSAM1 | het | c.2138_2139delT | p.Ile713Thrfs*22 | P | NA | NA | NA | NA | NA |
| 30 | HMN | AR | SPG11 | comp.het | c.[31G>C]; [6167A>T] |
p.[Ala11Pro]; [Glu2056Val] |
PP/VUS | 6/121316 5/57750 | D1/Poly | 0,808 Possibdam 0,899 Possibdam | 84 P/ 44 Poly | 2,14 MC 0,04 WC |
| 33 | CMT2 | AD | KIF1B | het | c.2086C>G | p.His696Asp | PP | NA | D1 | 0,978 PD | 81 P | 5,61 HC |
| 34 | CMT | SPO | KIF1B | het | c.2030G>A | p.Ser677Asn | PP | NA | D1 | 1 PD | 78 P | 1,044 WC |
| 36 | CMT inter | AD | DNM2 | het | c.1352G>T | p.Arg451Leu | PP | NA | D1 | NA | 93 P | 3,68 MC |
| 37 | CMT2 | AD | KIF5A | het | c.395A>G | p.Lys132Arg | PP | NA | D1 | 1 PD | 78 P | 1,088 WC |
| 39 | HMN | AD | REEP1 | het | c.568G>A | p.Gly190Ser | PP | 3/119252 | 0,999 Poly | 0,148 B | 63ProbPoly | 0,61 WC |
| 40 | CMT inter | AD | KIF5A | het | c.854C>T | p.Thr285Ile | PP | NA | D1 | 1 PD | 93 P | 5,29 HC |
| 44 | CMT2 | AD | KIF5A | het | c.332G>C | p.Arg111Pro | PP | NA | D1 | 1 PD | 96 P | 5,61 HC |
| 45 | CMT1 | AD | INF2 | het | c.314 T>G | p.Val105Gly | PP | NA | D1 | 1 PD | 90 P | 3,11 MC |
| 46 | CMT2 | AR | MFN2 | comp.het | c.[1714C>T]; [1928T>C] |
p.[Gln572Glu]; [Leu643Pro] |
PP/PP | 1/246228 1/246238 |
D1/D1 | 0,073 B / 0,983 PD |
100 P 100 P | 5,13 HC 4,08 MC |
| 48 | HSAN | AR | FAM134B | hoz | c.896-897delAA | p.Lys299Argfs*6 | P | 1/1 20 334 | NA | NA | NA | NA |
| 55 | HMN | SPO | DYNC1H1 | het | c.5578C>A | p.Gln1860Lys | PP | NA | D1 | 0,001 B | 75 P | 6,34 HC |
| 57 | HMN | SPO | MYH14 | het | c.4517G>T | p.Arg1506Leu | PP | NA | 0,929 D | 0,987 PD | 81 P | 2,95 MC |
| 58 | CMT2 | AD | BICD2 | het | c.2042C>T | p.Ser681Leu | PP | NA | D1 | 1 PD | 90 P | 5,61 HC |
| 59 | CMT2 | SPO | SPTLC1 | het | c.451C>T | p.Arg151Cys | PP | 2/118640 | D1 | 0,264 B | 100 P | 4,00 MC |
| 4 | CMT2 | AD | NEFL | het | c.67C>G | p.Arg23Gly | VUS | NA | NA | NA | NA | 2,09 WC |
| 12 | CMT1 | AD | LMNA | het | c.1694A>T | p.His565Leu | PP | NA | NA | NA | 84 P | 2,30 MC |
| 16 | CMT1 | AD | GJB1 | het | c.830G>A | p.Ser277Asn | PB | 2/26732 | 0,876 Poly | 0,002 B | 63 ProbPoly | 2,38 MC |
| 21 | CMT1 | AD | TRPV4 KIF1B LRSAM1 | het | c.812G>A c.3350A>G c.1658A>C |
p.Arg271His p.Tyr1117Cys p.Gln553Pro | VUS VUS VUS | 1/120838 1/120270 NA | D1 Poly D1 | 0,764 Possibdam 0 B 0,994 PD | 78 P NA 93 P | 5,13 HC - 1,57 NC 3,60 MC |
| 25 | HSAN | AD | NEFL | het | c.995_997delAGC | p.Gln332del | P | NA | NA | NA | NA | NA |
| 27 | CMT2 | AD | INF2 | het | c.2709G>C | p.Gln903His | VUS | 1/119080 | D 0,991 | 0,998 PD | 57 ProbPoly | 2,47 MC |
| 35 | CMT2 | AD | INF2 | het | c.3637C>T | p.Arg1213Trp | VUS | 2/61282 | Poly | 0,998 PD | 72 ProbPatho | 1,66 WC |
| 38 | CMT2 | SPO | SEPT9 ARHGEF10 | het | c.53G>A c.3289A>G | p.Arg18Thr p.Ile1097Val | VUS VUS | 1/118806 1/120124 | Poly Poly | 0,015 B 0,023 B | 69 ProbPatho 66 ProbPatho | 0,28 NC 0,04 WC |
| 49 | HSAN | AD | HSPB1 | het | c.224G>A | p.Arg75His | VUS | NA | D1 | 0,539 Possibdam | 54 ProbPoly | 2,38 MC |
| 50 | CMT inter | AD | YARS | het | c.710G>A | p.Arg237Gln | VUS | 3/121190 | 0,983 D | 0,018 B | 78 P | 2,47 MC |
| 52 | CMT inter | AD | INF2 | het | c.2459G>A | p.Arg820Gln | VUS | NA | Poly | 0,001 B | 39 Poly | −0,68 NC |
| 61 | CMT1 | SPO | FGD4 | Duplication of exons 3 to 14 | Not described in conrad.hg19 | |||||||
| 62 | CMT2 | AR | TFG | Duplication of exons 2 and 3 | Not described in conrad.hg19 | |||||||
| 28 | CMT2 | AD | TFG | Sequence variation in LITAF and DCTN1 +duplication of exons 2 and 3 |
Not described in conrad.hg19 |
AD, autosomal dominant; AR, autosomal recessive; B, benign; CMT1, Charcot-Marie-Tooth disease type 1; CMT2, Charcot-Marie-Tooth disease type 2; comp het, compound heterozygous; comp het, composite heterozygosis; D1, disease causing; HC, highly conserved; het, heterozygous; hoz, homozygous; HSAN, hereditary sensory and autonomic neuropathy; IPN, inherited peripheral neuropathy; MC, moderately conserved; NA, not available; NT, not conserved; P, pathogenic; Poly, polymorphism; Possibdam, possibly damaging; PB, probably benign; PD, probably damaging; PP, probably pathogenic; ProbPoly, probably polymorphism; ProbPatho, probably pathogenic; SPO, sporadic; VUS, variant of unknown significance; WC, weakly conserved.