Table 1 Pathogenic variants and VUS identified from 2015 to 2018 in our laboratory by NGS.
Patient | Age at referral | Indication | Gene | NM | Haplotype | cDNA change | Amino acid change | ACMG (default Intervar) | Details of Intervar | ACMG (Intervar reintepreted or manual-Maryland) | Additional criteria leading to the variant class change | ExAC | GnomAD | Mutation Taster | UMD-predictor | HSF | Literature |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
P1 | 11m | CL 2B | PYCR1 | NM_006907.3 | hoz | c.616G>A | p.(GLy206Arg) | LP | PM1 PM2 PP3 PP5 | P | PS1 PP1 | 1/23214 (4.308e-05) | 2/186106 (1.07e-5) | D0.99 | P 100 | Probably no impact on splicing | Kretz et al. 2011; Reversade et al. 2009 |
P2 | 26y | RTS | RECQL4 | NM_004260.3 | comp.het | c.2263C>T | p.(Arg755Trp) | VUS | PM1 PM2 PP3 BP1 | LP | PM3 | NA | 1/240964 (4.15e-6) | NA | NA | Potential alteration of splicing | THIS REPORT |
c.2415_2419dup | p.(Arg807fs113Ter) | NA | P | PM2 PVS1 PP3 | NA | NA | NA | NA | Potential alteration of splicing | THIS REPORT | |||||||
P3 | 9y2m | CL | ALDH18A1 | NM_002860.4 | het | c.413G>A | p.(Arg138Gln) | LP | PM1 PM2 PP2 PP3 PP5 | P | PS1 | NA | NA | D0.999 | P 84 | Potential alteration of splicing | Fischer-Zirnsak et al. 2015 |
P4 | 19y | BOFS | TFAP2A | NM_003220.3 | het | c.710G>A | p.(Arg237Gln) | LP | PM1 PM2 PP2 PP3 PP5 | P | PS1 | NA | NA | D0.999 | P 87 | Potential alteration of splicing | Reiber et al. 2010 and p.(Arg237Gly) in Milunsky et al., 2010 |
P5 | 6m | CL | GORAB | NM_152281.2 | comp.het | c.546A>T | p.(Glu182Asp) | VUS | PM2 | LP | PM3 PP3 PP4 | NA | NA | D0.999 | PP72 | Potential alteration of splicing | THIS REPORT |
c.859C>T | p.(Arg287Ter) | VUS | PM2 PP3 PP5 | P | PVS1 PM3 | 2/121244 (1.65e-05) | 3/251106 (1.19e-5) | D1 | P100 | Probably no impact on splicing | THIS REPORT | ||||||
P6 | 8m | RTS | RECQL4 | NM_004260.3 | comp.het | c.1573delT | p.Cys525AlafsTer33 | NA | P | PVS1 PM2 PM3 PP5 | 27/104602 (2.581e-04) | 69/276484 (2.5e-4) | NA | NA | Potential alteration of splicing | Kitao et al. 1999; Siitonen et al. 2009 | |
c.2269C>T | p.(Gln757Ter) | P | PVS1 PM2 PP3 PP5 | P | / | 9/113308 (7.943e-05) | 32/271122 (1.18e-4) | NA | NA | Potential alteration of splicing | Pujol et al.2000; Wang et al. 2003;Siitonen et al. 2009 | ||||||
P7● | 19y | Cockayne Sd | ERCC6 | NM_000124.4 | het | c.2291T>C | p.(Leu764Ser) | VUS | PM1 PM2 PP3 BP1 | LP | PM3 (deletion of the other allele) | NA | NA | D0.999 | P90 | Probably no impact on splicing | THIS REPORT |
P8 | 41y | Werner Sd | WRN | NM_000553.5 | comp.het | c.2313T>A | p.(Cys771Ter) | P | PVS1 PM2 PP3 | P | / | NA | 1/251244 (3.98e-6) | D1 | P100 | Probably no impact on splicing | THIS REPORT |
c.2665C>T | p.(Arg889Ter) | P | PVS1 PM2 PP3 PP5 | P | / | 4/120718 (3.314e-05) | 6/251074 (2.39e-5) | D1 | P100 | Potential alteration of splicing | http://www.pathology.washington.edu/research/werner/database/ | ||||||
P9 | 43y | EDS | COL5A1 | NM_000093.4 | het | c.1884_1891del | p.(Asp629Phefs16Ter) | NA | LP | PVS1 PM2 | NA | NA | NA | NA | Potential alteration of splicing | THIS REPORT | |
P10 | 24y | SHORT Sd | PIK3R1 | NM_181523.2 | het | c.1945C>T | p.(Arg649Trp) | LP | PM1 PM2 PP3 PP5 | P | PS1 PP2 | NA | NA | D0.999 | P93 | Potential alteration of splicing | Dyment et al. 2013 |
P11 | 63y | UPS | LMNA | NM_170707.4 | het | c.1003C>T | p.(Arg335Trp) | VUS | PM2 PP3 PP5 | P | PS1 PM1 | NA | NA | D 0.999 | P96 | Probably no impact on splicing | Zaragova et al. 2017; Lambert et al., 2018 |
P12 | 37y | Buschke Ollendorf Sd | LEMD3 | NM_014319.4 | het | c.1323C>A | p.(Tyr441Ter) | VUS | PM2 PP3 | P | PVS1 PS1 PP5 | NA | NA | D1 | P100 | Potential alteration of splicing | Hellemans et al. 2006 |
P13 | 2m | CL | ALDH18A1 | NM_002860.3 | hoz | c.1499G>T | p.(Gly500Val) | LP | PM1 PM2 PP2 PP3 | P | PP1 PM3 | NA | 0/239782 (0) | D0.99 | P90 | Potential alteration of splicing | THIS REPORT |
P14 | 39y | EDS | COL5A1 | NM_000093.4 | comp.het | c.4030C>T | p.(Pro1344Ser) | VUS | PM2 PP3 BP1 | VUS | / | NA | NA | D 0.999 | P96 | Potential alteration of splicing | THIS REPORT |
c.2374C>T | p.(Arg792Ter) | P | PVS1 PM2 PP3 PP5 | P | / | NA | NA | D1 | P100 | Potential alteration of splicing | Wenstrup et al. 2010 | ||||||
P15 | 36y | Brittle cornea | PRDM5 | NM_018699.2 | hoz | c.1036C>T | p.(Arg346Ter) | P | PVS1 PM2 PP3 | P | / | 3/119938 (2.501e-05) | 3/244748 (1.23e-5) | D1 | P100 | Potential alteration of splicing | THIS REPORT |
P16 | 6y7m | Oculoden-todigital dysplasia | GJA1 | NM_000165.5 | het | c.287T>A | p.(Val96Glu) | LP | PM1 PM2 PP2 PP3 | P | PS1 PP5 | NA | NA | D0.99 | P100 | NA | Wiest et al. 2006 |
P17 | 41y | EDS | LMNA | NM_005572.3 (Lamin C isoform) | het | c.1715G>A | p.(Arg572His) | VUS | PM2 | VUS | / | NA | 0/149540 (0) | Polym 0.992 | Prob Polym | Probably no impact on splicing | THIS REPORT |
P18 | 59y | Werner Sd | LMNA | NM_170707.4 | het | c.1016C>T | p.(Ala339Val) | VUS | PM2 PP3 | VUS | / | NA | NA | D0.999 | P84 | Potential alteration of splicing | THIS REPORT |
P19 | 4m | UPS | RECQL4 | NM_004260.3 | hoz | c.2756-8G>T | p.? | NA | VUS | / | 17/107602 (1.58e-04) | 59/276606 (2.13e-4) | NA | NA | Probably no impact on splicing | THIS REPORT | |
P20 | 68y | EDS | ALDH18A1 | NM_002860.4 | het | c.1597G>A | p.(Val533Met) | VUS | PM1 PP2 | VUS | / | NA | 3/178100 (1.68e-5) | Polym 0,960 | PP69 | Probably no impact on splicing | THIS REPORT |
P21 | 47y | EDS | COL1A2 | NM_000089.3 | het | c.798A>C | p.(Glu266Asp) | VUS | PM2 | VUS | / | NA | 2/282868 (7.07e-6) | D0,999 | Polym45 | Potential alteration of splicing | THIS REPORT |
P22 | 20y | UPS | SYNE1 | NM_182961.4 | het | c.21209T>G | p.(Leu7070Trp) | VUS | BP1 | VUS | / | NA | NA | Polym 0,890 | P78 | Potential alteration of splicing | THIS REPORT |
P23a | 21m | UPS | ATR | NM_001184.4 | het | c.4750A>C | p.(Met1584Leu) | VUS | PM2 | B | lack of segregation with the disease in the family | NA | 3/251454 (1.19e-5) | D0,999 | PP72 | Potential alteration of splicing | THIS REPORT |
P24a | 17y | EDS | COL1A1 | NM_000088.3 | het | c.310G>A | p.(Asp104Asn) | VUS | PM2 | B | lack of segregation with the disease in the family | NA | NA | Polym0,999 | Polym33 | Potential alteration of splicing | THIS REPORT |
P25 | 57y | UPS | COL5A2 | NM_000393.5 | het | c.463C>T | p.(Arg155Cys) | VUS | PP3 | VUS | / | 1/49686 (2.013e-5) | 7/209120 (3.35e-5) | D0,999 | P100 | Potential alteration of splicing | THIS REPORT |
SYNE2 | NM_182914.2 | het | c.20632_20634delinsGAA | p.(Ser6878Glu) | NA | VUS | / | NA | NA | NA | NA | Potential alteration of splicing | THIS REPORT | ||||
P26a | 65y | UPS | ATR | NM_001184.4 | hoz | c.7701A>G | p.(Lys2567Lys) | VUS | BP4 BP7 | B | lack of segregation with the disease in the family | NA | NA | D1 | P77 | Potential alteration of splicing | THIS REPORT |
P27 | 21y | UPS | ELN | NM_001278913.1 | het | c.1063_1086del | p.(355_362del) | NA | VUS | / | NA | NA | NA | NA | NA | THIS REPORT | |
P28 | 28y | EDS | TNXB | NM_019105.7 | het | c.747C>T | p.(Cys249Cys) | LB | PM2 BP4 BP7 | VUS | / | 1/102780 (9.73e-06) | 1/245798 (4.07e-6) | D1 | Polym 11 | Potential alteration of splicing | THIS REPORT |
P29 | 57y | UPS | FBN1 | NM_000138.4 | het | c.5347A>T | p.(Ile1783Phe) | VUS | VUS | / | NA | NA | D0,999 | P78 | Potential alteration of splicing | THIS REPORT | |
P30 | 19y | EDS | ACAN | NM_013227.3 | het | c.7205G>A | p.(Arg2402His) | VUS | PM1 PM2 | VUS | / | 8/119916 (6.671e-05) | 20/248986 (8.03e-5) | D0,999 | P87 | Probably no impact on splicing | THIS REPORT |