Table 1.
Examples of common and rare SERPINA1 variants and their clinical significance.
| SERPINA1 variants | Type of mutation10 (nucleotide/amino acid change) | Clinical significance | Approximate serum AAT level | Reference | ClinVar accession number |
|---|---|---|---|---|---|
| Common | |||||
| I | Point mutation (c.187C>T; p.Arg63Cys) | Uncertain | <120 mg/dL, (22 µM)24 | Graham et al.25 | VCV000017974.6 |
| F | Point mutation (c.739C>T; p.Arg247Cys) | Uncertain | 160 mg/dL, (30 µM)26 | Okayama et al.26 | VCV000017961.5 |
| S | Point mutation (c.863A>T; p.Glu288Val) | Uncertain | 82 mg/dL, (15 µM)27 | Tan et al.28 | VCV000017969.9 |
| Z | Point mutation (c.1096G>A; p.Glu366Lys) | Pathogenic: linked to development of emphysema and liver disease | 20–45 mg/dL, (2.5–7 µM)6 | Laurell and Eriksson29 | VCV000017967.13 |
| Rare | |||||
| MHeerlen | Point mutation (c.1178C>T; p.Pro393Leu) | Pathogenic: linked to development of lung disease | 5 mg/dL, (~1 µM)30 | Hofker et al.30 | VCV000017965.2 |
| MMalton | Point mutation (c.226_228del; p.Phe76_del) | Pathogenic: linked to development of emphysema and liver disease | 64–87 mg/dL, (11–16 µM)31 | Curiel et al.15 | RCV000201853.1 |
| MProcida | Point mutation (c.194T>C; p.Leu65Pro) | Pathogenic: intermediate pathogenicity | <10 mg/dL, (<2 µM)19 | Takahashi et al.19 | RCV000019571.3 |
| MWürzburg | Point mutation (c.1177C>T; p.Pro393Ser) | Pathogenic: linked to development of lung disease | 94 mg/dL, (17 µM)17 | Poller et al.17 | RCV000336993.8 |
| NNagato | Point mutation (c.899T>C; p.Leu300Arg) | Uncertain significance: likely benign | ~180 mg/dL, (~33 µM)32 | Yuasa et al.32 | VCV000594462.3 |
| PBrescia | Point mutation (c.745G>C; p.Gly249Arg) | Pathogenic: linked to lung and liver disease | 61 mg/dL, (11 µM)16 | Medicina et al.16 | VCV000189018.1 |
| PLowell | Point mutation (c.839A>T; p.Asp280Val) | Pathogenic: linked to lung disease | 77 mg/dL, (14 µM)33 | Cook et al.13 | VCV000017975.4 |
| Q0Amersfoort | Null mutation – stop codon insertion (c.552C>G; p.Tyr184Ter) *Occurs in the same codon as Q0Granite Falls (c.552delC; p.Tyr184Terfs) | Pathogenic: emphysema | No AAT expression | Prins et al.20 | VCV000017976.1 |
| Q0Mattawa | Null mutation – frameshift resulting in a premature stop codon (c.1131A>T; p.Leu377Phe) | Pathogenic: emphysema | No AAT expression | Cox and Levison34 | VCV000017978.1 |
| Q0Bellingham | Null mutation – stop codon insertion (c.721A>T; p.Lys241Ter) | Pathogenic: emphysema | No AAT expression | Satoh et al.21 | VCV000017977.2 |
| SIiyama | Point mutation (c.230C>T; p.Ser77Phe) | Pathogenic: emphysema | 33 mg/dL, (6 µM)35 | Yuasa et al.36 | VCV000017992.1 |
| VMunich | Point mutation (c.77A>C; p.Asp26Ala) | None | 150–250 mg/dL, (29–46 µM)37 | Holmes et al.37 | VCV000017983.1 |
| WBethesda | Point mutation (c.1078G>A; p.Ala360Thr) | Uncertain | ~170 mg/dL, (~32 µM)38 | Holmes et al.39 | VCV000017985.1 |
| X | Point mutation (c.682G>A; p.Glu228Lys) | None | Serum AAT levels likely within the normal range40 | Crystal et al.40 | VCV000017963.1 |
| XChristchurch | Point mutation (c.1159G>A; p.Glu387Lys) | Uncertain: likely benign | Serum AAT levels likely within the normal range40 | Brennan and Carrell41 | VCV000017964.4 |
| ZAugsburg | Point mutation (c.1096G>A; p.Glu366Lys) | Pathogenic: linked to development of emphysema and liver disease | 83 mg/dL (15 µM)4 | Faber et al.42 | VCV000017967.13 |
| ZWrexham | Point mutation (c.17C>T; p.Ser6Leu) | Uncertain | Serum AAT levels likely as for PI*Z43 | Graham et al.43 | VCV000017970.1 |
Amino acid numbers described in protein mutations have been updated according to recommendations outlined by the Human Genome Variation Society and therefore may differ slightly in comparison to corresponding mutations reported in the literature.8
AAT, alpha-1 antitrypsin.