TABLE 3.
Characteristics of common controversial GLA variants according to genetic databases and in silico prediction softwares
| c.427G>A; p.(Ala143Thr) / p.(A143T) / Thr143 | c.937G>T; p.(Asp313Tyr) / p.(D313Y) / Tyr313 | c.196G>C; p.(Glu66Gln) / p.(E66Q) / Gln66 | c.352C>T; p.(Arg118Cys) / p.(R118C) / Cys118 | c.376A>G; p.(Ser126Gly) / p.(S126G) / Gly126 | |
|---|---|---|---|---|---|
| GnomAD v2.1.1 | |||||
| AF (%) in exomes, genomes (total) | 0.055, 0.018 (0.051) | 0.30, 0.31 (0.30) | 0.012, 0.0045 (0.011) | 0.022, 0.032 (0.023) | 0.033, 0.063 (0.036) |
| Highest AF (%) by population | 0.095 in European (non‐Finnish) |
0.69 in Ashkenazi Jewish 0.45 in European (non‐Finnish) |
0.15 in East Asian | 0.044 in European (non‐Finnish) | 0.074 in European (non‐Finnish) |
| Pathogenicity according to FD‐specific databases | |||||
| dbFGP | Benign | Benign | Benign | Benign | Likely benign |
| The Japanese Fabry Database | LO [5]; classic [4]; B [3]; VUS [1]; np [8] | Classic [5]; B [2]; LO [1]; np [9] | B [5]; classic [5]; LO [3]; np [3] | LO [2]; np [5] | LO [1]; np [6] |
| Pathogenicity according to general databases | |||||
| ClinVar | VUS [10]; LP [4]; P [2] | LB [13]; VUS [3]; B [2] | VUS [4]; LB [2] | VUS [12]; LP [2]; LB [1] | LB [6]; VUS [4]; B [1] |
| LOVD | LB [2]; VUS [1] | LB [3]; B [2]; VUS [1] | np | VUS [3]; P [1] | 2 LB [2]; VUS [1] |
| OMIM | FD | VUS (recently reclassified) | Functional polymorphism and not disease causing | not provided | not provided |
| ACMG classification according to VarSome (date of query) |
LP (2019‐12‐05) VUS because highest ethnic frequency = 0.10% (2020/01/20) P because a user has reported this variant is classified LP in one article (Spada et al. 5 ) and that is confirmed by a functional study (2020‐08‐03) |
VUS (2019‐12‐05) B because highest ethnic frequency = 0.69% (2020‐01‐20) LP because alternative variant (Asp313Asn) is classified P by UniProt Variants (and confirmed using ACMG) (2020‐08‐04) |
VUS (2019‐12‐05) B because highest ethnic frequency = 0.15% (2020‐01‐20) LP because highest ethnic frequency no longer takes into account again (2020‐08‐04) |
LB (2019‐12‐05) B (2020‐01‐20) LB (2020‐08‐04) |
VUS (2019‐12‐05) B because highest ethnic frequency = 0.074% (2020‐01‐20) VUS because highest ethnic frequency no longer taken into account (2020‐08‐04) |
| Polyphen‐2 | Probably damaging (1) | Probably damaging (0.996) | Probably damaging (0.996) | Probably damaging (0.993) | Benign (0.043) |
| Provean | Deleterious (−3.119) | Deleterious (−3.183) | Deleterious (−2.754) | Deleterious (−4.667) | Deleterious (−2.823) |
| SIFT | Damaging (0.004) | Damaging (0.001) | Damaging (0.002) | Damaging (0.001) | Tolerated (0.060) |
| Mutation taster | Disease causing | Polymorphism | Disease causing | Polymorphism | Disease causing |
Note: Last accessed 2020‐08‐04. [ ]: The number of times referenced.
Abbreviations: AF, allele frequency; B, benign; dbFGP, International Fabry Disease Genotype–Phenotype Database; FD, Fabry disease; gnomAD, Genome Aggregation Database; LB, likely benign; LOVD, Leiden Open (source) Variation Database; LP, likely pathogenic; np, not provided; P, pathogenic; VUS, variant of unknown significance.