Table 1.
Details of the IQSEC2 variants identified in the 47 patients reported in this study
| Patient ID | Sex M/F | Variant position (hg19) | Change (NM_001111125.2) | CADD score (PHRED) | Prediction SIFT/Polyphen-2 (missense) | Protein domain (missense) | Inheritance | Adjusted ACMG variant classification (InterVar) | Novel (n)/ Reference |
|---|---|---|---|---|---|---|---|---|---|
| 1 | F | g.53350171_53350267delinsAT | c.55_151delinsAT, .(Ala19Ilefs*32) | – | De novoa | Pathogenic | n | ||
| 2 | M | g.53350225G>A | c.97C>T, p.(Gln33*) | 36 | De novoa | Pathogenic | n | ||
| 3 | M | g.53350138G>A | c.184C>T, p.(Arg62*) | 35 | De novoa | Pathogenic | n | ||
| 4 | M | g.53349712_53349734del | c.588_610del, p.(Arg197Alafs*34) | – | De novoa | Pathogenic | n | ||
| 5 | M | g.53285244C>T | c.738-1G>A, p.? | 25.4 | Maternal | Pathogenic | n | ||
| 6 | M | g.53285244C>T | c.738-1G>A, p.? | 25.4 | Maternal | Pathogenic | n | ||
| 7 | M | g.53285244C>G | c.738-1G>C, p.? | 25.2 | De novo | Pathogenic | n | ||
| 8 | F | g.53285177del | c.804delC, p.(Tyr269Thrfs*3) | – | De novoa | Pathogenic | n | ||
| 9 | M | g.53285177del | c.804delC, p.(Tyr269Thrfs*3) | – | De novo | Pathogenic | n | ||
| 10 | M | g.53285177del | c.804delC, p.(Tyr269Thrfs*3) | – | De novoa | Pathogenic | 33 | ||
| 11 | F | g.53285127del | c.854del, p.(Pro285Leufs*21) | 32 | De novoa | Pathogenic | n | ||
| 12 | M | g.53285086G>A | c.895C>T, p.(Gln299*) | 35 | De novoa | Pathogenic | 33 | ||
| 13 | M | g.53280352_53280353del | c.1405_1406del, p.(Lys469Valfs*4) | – | De novoa | Pathogenic | n | ||
| 14 | M | g.53280248G>A | c.1510C>T, p.(Gln504*) | 37 | Unknown | Pathogenic | n | ||
| 15 | M | g.53279559_53280191delinsGCC | c.1567_2199delinsGGC, p.(Thr523_Thr733delinsGly) | – | De novoa | Pathogenic | n | ||
| 16 | F | g.53279995_53280014del | c.1744_1763del, p.Arg582Cysfs*9 | – | De novo | Pathogenic | n | ||
| 17 | F | g.53279758_53279776del | c.1983_1999del, p.(Leu662Glnfs*25) | – | Unknown | Pathogenic | n | ||
| 18 | F | g.53279680del | c.2078delG, p.(Gly693Valfs*29) | – | Unknown | Pathogenic | n | ||
| 19 | F | g.53279486G>A | c.2272C>T, p.(Arg758*) | 35 | De novo | Pathogenic | n | ||
| 20 | F | g.53279486G>A | c.2272C>T, p.(Arg758*) | 35 | De novoa | Pathogenic | n | ||
| 21 | F | g.53279480C>T | c.2278G>A, p.(Gly760Ser) | 32 | Tolerated/probably damaging | SEC7 | De novoa | Likely pathogenic | n |
| 22 | F | g.53278050C>T | c.2312G>A, p.(Gly771Asp) | 29.1 | Deleterious/probably damaging | SEC7 | De novoa | Likely pathogenic | 28 |
| 23 | F | g.53278045G>A | c.2317C>T, p.(Gln773*) | 41 | Unknown | Pathogenic | n | ||
| 24 | F | g.53278030_53278045del | c.2317_2332del, p.(Gln773Glyfs*25) | – | Unknown | Pathogenic | n | ||
| 25 | M | g.53278008G>A | c.2354C>T, p.(Pro785Leu) | 29.8 | Deleterious/possibly damaging | SEC7 | De novo | Likely pathogenic | n |
| 26 | M | g.53272627G>A | c.2776C>T, p.(Arg926*) | 40 | De novoa | Pathogenic | n | ||
| 27 | F | g.53272549G>A | c.2854C>T, p.(Gln952*) | 41 | De novoa | Pathogenic | n | ||
| 28 | M | g.53271019G>A | c.2962C>T, p.(Gln988*) | 42 | De novoa | Pathogenic | n | ||
| 29 | F | g.53268413del | c.3079delC, p.(Leu1027Serfs*75) | – | De novo | Pathogenic | n | ||
| 30 | M | g.53267441G>A | c.3163C>T, p.(Arg1055*) | 41 | Maternal | Pathogenic | 33 | ||
| 31 | F | g.53267441G>A | c.3163C>T, p.(Arg1055*) | 41 | Unknown | Pathogenic | n | ||
| 32 | M | g.53267441G>A | c.3163C>T, p.(Arg1055*) | 41 | De novoa | Pathogenic | n | ||
| 33 | M | g.53267398C>G | c.3206G>C, p.(Arg1069Pro) | 34 | Tolerated/probably damaging | PH | Maternal | Likely pathogenic | n |
| 34 | M | g.53267325A>C | c.3277+2T>G, p.? | 24.2 | De novoa | Pathogenic | n | ||
| 35 | M | g.53267322C>T | c.3277+5G>A, p.? | 19.41 | Maternal | Likely pathogenic | n | ||
| 36 | F | g.53265677G>T | c.3278C>A, p.(Ser1093*) | 42 | De novoa | Pathogenic | n | ||
| 37 | M | g.53265568G>T | c.3387C>A, p.(Tyr1129*) | 36 | De novo | Pathogenic | 27 | ||
| 38 | M | g.53265522G>A | c.3433C>T, p.(Arg1145*) | 37 | De novoa | Pathogenic | n | ||
| 39 | F | g.53265522G>A | c.3433C>T, p.(Arg1145*) | 37 | Not detected in mother, father unavailable | Likely pathogenic | n | ||
| 40 | F | g.53265009del | c.3457del, p.(Arg1153Glyfs*244) | – | De novoa | Pathogenic | n | ||
| 41 | F | g.53263829dup | c.4039dup, p.(Ala1347Glyfs*40) | – | De novoa | Pathogenic | n | ||
| 42 | F | g.53263467del | c.4401del, p.(Gly1468Alafs*27) | – | Not detected in mother, father unavailable | Likely pathogenic | n | ||
| 43 | M | g.53272651C>A | c.2752G>T, p.(Val918Phe) | 34 | Deleterious/possibly damaging | SEC7 | Maternal | VUS | n |
| 44 | F | g.53265540C>T | c.3415G>A, p.(Ala1139Thr) | 32 | Tolerated/probably damaging | C-ter | Affected sister also has thepathogenic variant, an affected brother deceased (carrier status unknown); parents unavailable | VUS | n |
| 45 | M | g.53265003G>A | c.3463C>T, p.Arg1155Trp | 32 | Deleterious/probably damaging | C-ter | Maternal | VUS | n |
| 46 | M | g.53265003G>A | c.3463C>T, p.Arg1155Trp | 32 | Deleterious/probably damaging | C-ter | Maternal | VUS | n |
| 47 | F | g.53310692del | c.737+10385del, p.? | 8.355 | Maternal | VUS | n |
ACMG American College of Medical Genetics and Genomics, VUS variant of uncertain significance
aIndicates that paternity and maternity have been confirmed