Table 2.
Workgroup GLA variant phenotype classification consensus results; Stages 1–4
| Fabry Registry GLA variants (n=33) |
Variant type | No. of males with genotype | No. of males with genotype and usable clinical data* | GLA variant 2-point score (%) | GLA variant phenotype consensus† | ||
| Provisional | Final | ||||||
| Stage 1 | Stage 2 | Stages 3 and 4 | |||||
| p.Trp44Cys | Missense | 7 | 5 | 100 | Classic | Classic | Classic |
| p.Met284Thr | Missense | 6 | 6 | 100 | – | Classic‡ | Classic |
| c.777del | Frameshift | 6 | 5 | 100 | – | Classic‡ | Classic |
| c.1042dup | Frameshift | 5 | 3§ | 100 | – | Classic‡ | Classic |
| p.Ser65_Tyr123del | Large deletion | 4 | 4 | 100 | – | Classic‡ | Classic |
| c.1212_1214del | Small deletion | 7 | 1§ | 100 | – | Classic‡ | Classic |
| p.Ser345Pro | Missense | 11 | 10 | 87 | Unclassified | Classic | Classic |
| c.370-2A>G | Splice site | 5 | 5 | 86 | – | Classic‡ | Classic |
| c.802–3_802-2del | Splice site | 5 | 4 | 83 | – | Classic‡ | Classic |
| c.57_82del | Frameshift | 4 | 4 | 83 | – | Classic‡ | Classic |
| p.Gln283* | Nonsense | 4 | 3§ | 80 | Classic | Classic | Classic |
| p.Ala156Thr | Missense | 5 | 4 | 80 | Classic | Classic | Classic |
| p.Thr194Ile | Missense | 5 | 5 | 80 | Classic | Classic | Classic |
| c.548–1G>A | Splice site | 4 | 4 | 80 | – | Classic‡ | Classic |
| c.365_371del | Frameshift | 6 | 5 | 80 | – | Classic‡ | Classic |
| p.Glu358del | Small deletion | 13 | 9 | 77 | Classic | Classic | Classic |
| c.1188_1189insT | Frameshift | 5 | 4 | 75 | Classic | Classic | Classic |
| p.Ala15Glu | Missense | 6 | 4 | 71 | – | Classic‡ | Classic |
| p.Trp162* | Nonsense | 7 | 6 | 70 | Classic | Classic | Classic |
| p.Pro259Arg | Missense | 28 | 21 | 69 | Classic | Classic | Classic |
| p.Trp340Arg | Missense | 4 | 4 | 67 | – | Classic‡ | Classic |
| p.Thr410Ile | Missense | 5 | 5 | 63 | Classic | Classic | Classic |
| c.568del | Frameshift | 4 | 3§ | 60 | – | Classic‡ | Classic |
| c.639+4A>T | Intronic | 6 | 4 | 60 | – | Classic‡ | Classic |
| c.1000–10G>A | Intronic | 4 | 4 | 60 | – | Classic‡ | Classic |
| p.Ile198Thr | Missense | 8 | 4 | 43 | – | Later-onset‡ | Later-onset |
| c.999+2T>C | Splice site | 5 | 4 | 40 | – | Unclassified‡ | Classic |
| p.Ser238Asn | Missense | 11 | 8 | 36 | Classic | Later-onset | Later-onset |
| c.639+919G>A | Intronic | 13 | 10 | 31 | – | Later-onset‡ | Later-onset |
| p.Arg363His | Missense | 12 | 5 | 29 | Later-onset | Later-onset | Later-onset |
| p.Asp322Glu | Missense | 7 | 6 | 27 | Unclassified | Unclassified | Later-onset |
| p.Ala143Thr | Missense | 24 | 13 | 27 | Unclassified | Unclassified | GVUS¶ |
| p.Ile117Ser | Missense | 6 | 6 | 25 | – | Later-onset‡ | Later-onset |
*Usable data on angiokeratomas or cornea verticillata status available in the Fabry Registry.
†Phenotypes associated with ‘pathogenic’ GLA variants include ‘classic’ and ‘later-onset’ phenotypes.
‡Novel GLA variants (n=19) resulting from using a more recent Fabry Registry reconciled data download (July 2016) added during Stage 2 of the process (hence the 'dash' in the Stage one column).
§Null variant present in ≥4 male patients with <4 patients having 2-point scoring data available. Included in the process as the deleterious impact of the variant dominated the expert’s overall clinical phenotype assessment as ‘classic’.
¶Genetic variant of unknown significance; experts’ opinion in favour of a likely benign GLA variant.