Table 2. Summary of missense POMT1 mutation effects.
| Mutation | Phenotype | Enzymatic activity | I-Mutant (ΔΔG) | SNPs3D (SVM score) | Mupro (C score) | SNAP (RI, EA) | PhD-SNP (RI) | ConSeq (conservation level) | AAs in alignment |
|---|---|---|---|---|---|---|---|---|---|
| N144Da | LGMD-MR | ? | Decrease (−0.41) | Deleterious (−1.73) | Increase (0.3) | Non-neutral (3, 78%) | Disease (5) | 9 | N |
| T414Ma | LGMD-MR | ? | Decrease (−0.33) | Deleterious (−2.17) | Decrease (−0.66) | Non-neutral (4, 82%) | Neutral (1) | 8 | A, S, T |
| A669T |
CMD-MR |
0.004 pmol/h/mg proteins32c |
Decrease (−1.37) |
Deleterious (−2.39) |
Decrease (−0.92) |
Non-neutral (1, 63%) |
Disease (5) |
9 |
A, S |
| G65R |
LGMD-MR |
0.002 pmol/h/mg proteins32b,c |
Decrease (−1.31) |
Deleterious (−2.66) |
Decrease (−0.69) |
Non-neutral (1, 63%) |
Disease (7) |
9 |
H, G |
| G76R | WWS | None2 10%35 | Decrease (−0.57) | Deleterious (−0.90) | Increase (+0.69) | Non-neutral (1, 63%) | Disease (5) | 5 | A, T, M, I, G, V |
| L171A | LGMD-MR | 40%35 | Decrease (−2.22) | Non-deleterious (+0.51) | Decrease (−1) | Neutral (0, 53%) | Disease (8) | 8 | I,L,V |
| A200P | LGMD-MR | None32 | Decrease (−1.05) | Deleterious (−0.89) | Decrease (−0.1) | Non-neutral (3, 78%) | Disease (7) | 7 | A, T, D, G, V |
| V428D | WWS | None2 | Decrease (−1.11) | Deleterious (−3.26) | Decrease (−0.87) | Non-neutral (6, 93%) | Disease (9) | 8 | F, I, V |
| W582C | LGMD-MR | 0.002 pmol/h/mg proteins32b,c | Decrease (−1.53) | Non-deleterious (+0.94) | Decrease (−1) | Non-neutral (3, 78%) | Disease (6) | 7 | F, W |
Abbreviations: AAs, amino acids; C score, confidence score; CMD-MR, congenital muscular dystrophy with mental retardation; EA, expected accuracy; LGMD-MR, limb-girdle muscular dystrophy with mental retardation; RI, reliability index; SVM, support vector machine; WWS, Walker–Warburg syndrome.
The mutations are listed with their associated phenotype, enzymatic activity and several in silico predictions. I-Mutant, MUpro and SNPs3D predict changes in protein stability in terms of ΔΔG, whereas SNAP and PhD-SNP predict a variant as disease-related or as neutral polymorphism. In the table we report reliability parameters for each prediction in parentheses. I-Mutant calculates the free energy change value (ΔΔG), where a ΔΔG<0 indicates decrease of stability. SNPs3D uses a SVM to find the separation pattern between a set of disease and non-deleterious SNPs. A positive score indicates variants classified as non-deleterious. MUpro predictions were reported with the confidence score (C score). A negative score indicates the mutation decreases protein stability, where lower scores imply higher confidence. In SNAP, variations are listed as ‘neutral' or ‘non-neutral' with reliability indices (RI; range 0–9) and EA (range 1–100%) indicative of confidence in prediction. Higher RI correlates strongly with higher prediction accuracy. EA is a number of correctly predicted neutral or non-neutral samples (at a given reliability index) in the SNAP testing set. SNAP only reports predictions that are made with at least 50% accuracy. PhD-SNP classifies a mutation as disease-related or as neutral polymorphism. As with SNAP, the RI indicates the confidence of predictions. ConSeqscores the sequence conservation from 0 to 9, with 9 being highly conserved and 0 being highly unconserved (ie, variable). The last column shows the residue types present in that position of the multiple sequence alignment.
Novel mutation.
Measured in lymphoblasts from a compound heterozygous carrier of p.G65R and p.W582C.
Average range of POMT activity in controls is 0.041±0.013 pmol/h/mg proteins.32