Table 3.
Case-Specific Variants with Actionable Hypotheses
| Gene | Protein Variant | Frequencya(Race)b | General Score (Confidence Level)c | Structure or Function Hypotheses (Probability Scores) |
|---|---|---|---|---|
|
COL6A1d |
p.Val117Ala | 2/141 (W) | 0.776 (VC) | loss of helix (p = 0.0076), gain of loop (p = 0.0079), loss of stability (p = 0.0292), gain of disorder (p = 0.0353), gain of ubiquitination at Lys121 (p = 0.04441) |
| p.Arg872Trp | 1/141 (B) | 0.790 (C) | loss of methylation at Arg872 (p = 0.0207), loss of disorder (p = 0.0259), gain of catalytic residue at Arg872 (p = 0.0467) | |
| p.Gln768His | 1/141 (W) | 0.537 (A) | gain of sheet (p = 0.0016), loss of helix (p = 0.0017), gain of loop (p = 0.024) | |
|
COL6A2d |
p.Arg853Gln | 1/141 (W) | 0.869 (C) | gain of ubiquitination at Lys851 (p = 0.0354) |
| p.Glu106Lys | 5/141 (W) | 0.759 (C) | gain of methylation at Glu106 (p = 0.0122) | |
|
COL6A3 |
p.Lys2737Gln | 1/141 (W) | 0.650 (A) | loss of ubiquitination at Lys2737 (p = 0.0283), loss of sheet (p = 0.0315), loss of methylation at Lys2737 (p = 0.0355) |
| p.Arg406Cys | 1/141 (W) | 0.643 (A) | gain of sheet (p = 0.0344), loss of helix (p = 0.0376) | |
| p.Arg1149Trp | 1/141 (W) | 0.625 (A) | loss of disorder (p = 0.0107) | |
| p.Ala1373Thr | 1/141 (H) | 0.543 (A) | gain of phosphorylation at Ala1373 (p = 0.0412) | |
| p.Glu2746Lys | 1/141 (W) | 0.513 (A) | gain of ubiquitination at Glu2746 (p = 0.0258), loss of sheet (p = 0.0315), gain of methylation at Glu2746 (p = 0.0427) | |
|
COL18A1d |
p.Gly1596Arg | 1/141 (B) | 0.810 (VC) | gain of MoRFe binding (p = 0.0081) |
| p.Gly111Arg | 1/141 (B) | 0.835 (C) | loss of helix (p = 0.0167), gain of sheet (p = 0.0266), Gain of MoRF binding (p = 0.0311) | |
| p.Ser1719Leu | 1/141 (B) | 0.603 (A) | loss of disorder (p = 0.0152) | |
|
CRELD1 |
p.Arg329Cysb | 2/135 (W) | 0.860 (NP) | NP; biochemical analysis shows misfolding |
| p.Glu414Lys | 1/135 (W) | 0.798 (VC) | gain of methylation (p = 0.016), gain of MoRF binding (p = 4 × 10−04) | |
| FBLN2 | p.Ile1039Thr | 1/141 (W) | 0.696 (A) | loss of stability (p = 0.0211) |
| FRZB | p.Phe100Ser | 1/141 (W) | 0.543 (A) | gain of disorder (p = 0.0078) |
| GATA5 | p.Gln3Argb | 2/141 (W) | 0.712 (C) | gain of MoRFe binding (p = 8 × 10−04), gain of methylation (p = 0.0283); transcription assay shows gain of function |
| p.Tyr142His | 1/141(W) | 0.743 (A) | gain of disorder (p = 0.0409) | |
a
Frequency is the number of individuals in which each variant was identified over the number of total cases resequenced for that gene.
b
Race codes are as follows: W, white; B, black; and H, Hispanic.
c
Confidence levels are as follows: A, actionable hypotheses; C, confident hypotheses; VC, very confident hypotheses; and NP, none predicted.
d
Gene is located on chromosome 21 (trisomic for this population).
e
Gain of MoRF binding represents gain of molecular recognition factor binding (interaction with other molecules is enhanced).