Table 3.
Analysis of disease-associated variants identified in children with ocular features of albinism.
| gene | genotype | protein | probands affected | report describing the variant in association with albinism | gnomAD total frequency % (allele count) | polyphen-2 HumVar score | CADD score |
|---|---|---|---|---|---|---|---|
| GPR143 | c.659-1 G > A | not applicable | 1 | Han et al.15 | not detected (0/183,366) | not applicable | 26.5 |
| TYR | c.1217 C > T | p.(Pro406Leu) | 3,11 | Giebel et al.18 | 0.3918% (1,104/281,766) | 0.997 | 27.2 |
| TYR | c.[575 C > A; 1205 G > A] | p.[(Ser192Tyr);(Arg402Gln)] | 3, 4, 5, 6, 7, 8, 9 | Norman et al.3 | 25.02% (70,744/282,804) & 17.65% (49,703/281,606) | 0.974 & 0.994 | 24.2 & 29.4 |
| TYR | c.1118 C > A | p.(Thr373Lys) | 4, 6 | King et al.19 | 0.0354% (100/282,382) | 0.004 | 23.5 |
| TYR | c.823 G > T | p.(Val275Phe) | 5 | Giebel et al.18 | 0.0099% (28/282,378) | 0.42 | 11.17 |
| TYR | c.1392dupT | p.(Lys465*) | 10 | novel | not detected (0/251,158) | not applicable | not applicable |
| SLC38A8 | c.534 C > G | p.(Ile178Met) | 2 | novel | 0.0016% (4/250,998) | 0.701 | 22.1 |
| SLC38A8 | exon 2 to exon 5 deletion | exon 2 to exon 5 deletion | 2 | novel | not applicable | not applicable | not applicable |
| OCA2 | c.1327 G > A | p.(Val443Ile) | 5, 9 | Lee et al.20 | 0.3055% (860/281,442) | 0.998 | 27.0 |
| OCA2 | c.2346deIG | p.(Thr783Hisfs*2) | 10 | novel | not detected (0/251,472) | not applicable | not applicable |
| OCA2 | c.1441 G > A, | p.(Ala481Thr) | 11 | Yuasa et al.22 | 0.8427% (2,384/282,886) | 0.466 | 24.7 |
| TYRP1 | c.208 G > A | p.(Ala70Thr) | 8 | Marti et al.21 | 0.0242% (68/281,344) | 0.606 | 23.0 |
Polyphen-222 (http://genetics.bwh.harvard.edu/pph2/) predicts the impact of an amino acid substitution on a human protein using physical and comparative considerations. The output is a 0 to 1 score; the higher the score the more likely it is that the variant is pathogenic. Combined Annotation-Dependent Depletion23 (CADD; https://cadd.gs.washington.edu/) combines information from many different in silico tools and uses a support vector machine classifier. The CADD score ranges from 1 to 99; a higher score indicates greater pathogenicity. Values ≥10 are predicted to be the 10% most deleterious substitutions and ≥ 20 in the 1% most deleterious. The overall gnomAD26 (http://gnomad.broadinstitute.org/) minor allele frequency is presented. Polyphen-2, CADD and gnoMAD were all accessed on 23/01/2019.