Table 1.
Twelve pathogenic variants identified in 8 probands with hereditary leukodystrophies
| Proband No. | Gene | Nucleotide change | Amino acid change | Genotype | gnomAD | ExAC | SIFT | Polyphen‐2 | CADD | ACMG |
|---|---|---|---|---|---|---|---|---|---|---|
| 1 | AARS2 | c.595C>T | p.R199C | Hom | 8.9e‐05 | 0.0001 | D | Pro_D | D | P(PS1+PM1+PM2+PM3+PP1+PP3+PP5) |
| 2 | CSF1R | c.2654_2654+3del | p.G852Dfs*67 | Het | 0 | 0 | NA | NA | NA | P(PVS1+PM1+PM2+PM4+PP3) |
| 3 | CSF1R | c.2381T>C | p.I794T | Het | 4.1e‐06 | 8.2e‐06 | D | Pro_D | D | P(PS3+PM1+PM2+PP3+PP4+PP5) |
| 4 | EIF2B3 | c.22A>T | p.M8L | Het | 0.0001 | 9.8e‐05 | T | B | D | US(PM2+PM3) |
| 4 | EIF2B3 | c.1037T>C | p.I346T | Het | 0 | 0 | T | B | D | LP(PM1+PM2+PP3+PP5) |
| 5 | GALC | c.599C>A | p.S200X | Het | 0 | 0 | NA | NA | D | P(PVS1+PM2+PP1+PP3+PP5) |
| 5 | GALC | c.1586C>T | p.T529M | Het | 9.8e‐05 | 6.6e‐05 | T | Pro_D | D | LP(PM1+PM2+PM3+PP1+PP3+PP5) |
| 6 | GALC | c.1321C>T | p.Q441X | Het | 0 | 0 | NA | NA | D | LP (PM1+PM2+PM3+PM4+PP3) |
| 6&7 | GALC | c.1901T>C | p.L634S | Het | 0.0006 | 0.0007 | D | Pro_D | D | LP(PM2+PM3+PP1+PP3+PP5) |
| 7 | GALC | c.2041G>A | p.V681M | Het | 0.0002 | 0.0002 | D | Pro_D | D | LP(PM2+PM3+PP1+PP3+PP5) |
| 8 | GALC | c.166G>C | p.D56H | Het | 0 | 0 | D | D | D | P (PS3+PM1+PM2+PM3+PP3) |
| 8 | GALC | c.461C>A | p.P154H | Het | 1.219e‐05 | 8.3e‐06 | D | Pro_D | D | LP(PM1+PM2+PM3+PP1+PP3) |
Novel variants are in bold.
Abbreviations: ACMG, American College of Medical Genetics and Genomics; B, benign; D, damaging, deleterious, or disease‐causing; ExAC, Exome Aggregation Consortium; gnomAD, The Genome Aggregation Database; LP, likely pathogenic; NA, not applicable; P, pathogenic; Polyphen‐2, Polymorphism Phenotyping v2; Pro_D, probably damaging; SIFT, Sorting Tolerant From Intolerant; T, tolerated; US, uncertain significance.