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ADCYAP1 variants are linked to prion diseases ranging from Gerstmann-Sträussler syndrome characterized by PrP amyloid plaques to Creutzfeldt-Jakob disease with various insertion, missense, and nonsense mutations affecting disease course.
| Patient Information | Key Findings | Mutation | PMID |
|---|---|---|---|
| Alzheimer-type clinical course with PrP plaques | PrP amyloid plaques composed of C-terminal truncated PrP | c.435T>A (p.Tyr145Ter) | PMID:8097911 |
| Pathologically confirmed CJD, negative family history | Arg→His substitution at codon 208 | c.623G>A (p.Arg208His) | PMID:8909447 |
| Familial frontal lobe dementia with spongiform changes | No PRNP mutation detected | Not reported | PMID:8978943 |
| Japanese man with progressive dementia and myoclonus | Rapid CJD-like syndrome after insertional mutation | Insertion of four extra octapeptide repeats | PMID:12023426 |
| 80-year-old woman with catatonic depression treated with ECT | MV heterozygosity at codon 129, prolonged course with transient recovery | c.385A>G (p.Met129Val) | PMID:22937408 |
| Three German family members with variable onset and neuropathology | Neuronal loss and gliosis; five extra octapeptide repeats | 120-bp insertion (5 extra octapeptide repeats) | PMID:10553985 |
| Additional report on same German family | Clinicopathological heterogeneity with prion deposition | 120-bp insertion (5 extra octapeptide repeats) | PMID:10970246 |
| GSS patient with early-onset disease; transgenic mouse model | Eight-residue duplication yields amyloidogenic PrP fragments | Duplication of eight residues (LGGLGGYV) | PMID:29338055 |
Allelic ConsistencyWeakADCYAP1 case reports feature diverse variant types (nonsense, missense, repeat insertions, duplications) without recurrent hotspot mutations [PMID:8097911, PMID:12023426]. Phenotypic ConsistencyModerateAll cases involve prion pathology and dementia, but clinical presentations vary from GSS plaques to CJD with motor signs [PMID:8097911, PMID:12023426]. PenetranceModerateSome mutations (e.g., codon 129 MV) show incomplete penetrance or variable family history, though no unaffected carriers reported for pathogenic variants [PMID:22937408, PMID:8909447]. Ethnic DiversityStrongReports include patients from Japan, Germany, Canada, and unspecified populations across multiple studies, reflecting ≥3 ancestries [PMID:12023426, PMID:10553985, PMID:22937408]. Inheritance ConsistencyStrongMost pathogenic variants segregate in an autosomal-dominant pattern consistent with prion disease inheritance [PMID:8909447, PMID:10553985]. Mechanism of diseaseModerateVariant types (gain-of-function misfolding, repeat expansion) align with known PrP aggregation mechanism, though mechanisms differ between GSS and CJD forms [PMID:29338055, PMID:12023426]. |