| Variant class/location | Examples (HGVS where present) | Reported proportion or counts | Reported phenotype-severity notes | Mechanism interpretation as stated |
|---|---|---|---|---|
| Whole-gene or intragenic deletion involving **NR2F1** | Whole-gene deletion (599 kb); deletions reported as 400–500 kb, 582 kb, and larger CNVs including adjacent genes; exact HGVS not provided in retrieved evidence | 15/92 clinically described patients (16.3%) had small-to-large deletions involving **NR2F1** alone or with adjacent genes (pqac-00000010, pqac-00000012) | Deletions are part of the classic BBSOAS spectrum with DD/ID and optic nerve abnormalities; early reports with larger deletions initially complicated gene attribution because additional genes were included (pqac-00000010, pqac-00000012) | Consistent with **haploinsufficiency**; review states BBSOAS is caused by gene deletion or loss-of-function mutations affecting one allele (pqac-00000009, pqac-00000012) |
| Start-codon / translation-initiation variants | p.M1?; “translation initiation variants” | 9/92 patients (9.8%) in the 2022 review summary (pqac-00000010) | Optic atrophy reported in **78%** of patients with translation-initiation variants, among the highest OA frequencies across classes (pqac-00000013) | Interpreted within the review as **loss-of-function / haploinsufficiency** class (pqac-00000012, pqac-00000013) |
| DNA-binding domain (DBD) missense / point variants | p.Gly105Ser; p.Cys146Tyr; p.Arg112Lys; p.Met151Thr; c.365G>T p.Cys122Phe; c.449G>T p.Gly150Val | 32/92 patients (34.8%) had variants in the DBD in the 2022 review summary; later genotype comparison grouped **36** DBD cases vs **64** non-DBD cases (pqac-00000010, pqac-00000002) | DBD variants are associated with relatively more severe phenotypes: optic atrophy **78%**; developmental delay **33/36 (91.67%)** vs **52/64 (81.25%)**; epilepsy **24/36 (66.67%)** vs **22/64 (34.38%)**, *p*=0.002; ASD **22/36 (61.11%)** vs **23/64 (35.94%)**, *p*=0.015; abnormal corpus callosum **16/36 (44.44%)** vs **16/64 (25.00%)**, *p*=0.045 (pqac-00000013, pqac-00000002) | Review notes DBD variants often severely impair transcription-factor function; Bonzano 2023 states variants are “predominantly located in the DNA-binding domain and lead to haploinsufficiency or dominant-negative effects” (pqac-00000009, pqac-00000002) |
| Ligand-binding domain (LBD) missense variants | p.Met406Thr | 17/92 patients (18.5%) had variants in the LBD (pqac-00000010) | LBD variants are associated with a milder ocular burden in aggregate: optic atrophy reported in **47%** of LBD cases versus higher frequencies for DBD/start-codon/truncating classes (pqac-00000013) | Bonzano 2023 states pathogenic variants overall can produce **haploinsufficiency or dominant-negative effects**; the 2022 review discusses possible effects on dimerization/co-factor binding for LBD-altering mutations (pqac-00000009, pqac-00000010) |
| Truncating variants (nonsense) | p.Glu400* | 11/92 patients (12.0%) had truncation variants (pqac-00000010) | Truncating classes are among those with high optic atrophy burden; review groups frameshift/truncations with OA in **72%** of patients (pqac-00000013) | Generally treated as **loss-of-function / haploinsufficiency** in the disease framework (pqac-00000009, pqac-00000012, pqac-00000016) |
| Frameshift / frameshift-truncating variants | Specific HGVS not retrieved in accessible excerpts | 7/92 patients (7.6%) had frameshift/truncation variants (pqac-00000010) | Review combines frameshift/truncation classes and reports optic atrophy in **72%**; these are part of the more severe ocular classes compared with LBD variants (pqac-00000013) | Usually interpreted as **loss-of-function / haploinsufficiency**; some literature outside accessible full text has discussed dominant-negative frameshift effects, but this was not directly retrievable here, so only haploinsufficiency can be stated confidently from retrieved evidence (pqac-00000012, pqac-00000016) |
| Mixed point variants/small in-frame deletions overall | Small indels and point variants concentrated in ATG start codon, DBD, and LBD | 77/92 patients (83.7%) had point variants or small in-frame deletions; total reported variants in the review: **112 NR2F1 variants** and **92 clinically described patients** (pqac-00000010) | Across all classes, the syndrome shows variable expressivity with DD, ID, optic nerve abnormalities, epilepsy, ASD/autistic traits, hypotonia, and hearing issues; review emphasizes emerging genotype-phenotype correlation rather than absolute class-specific determinism (pqac-00000011, pqac-00000013) | Disease mechanism is framed broadly as **NR2F1 haploinsufficiency**, with some missense variants potentially exerting **dominant-negative** effects depending on domain and dimerization consequences (pqac-00000009, pqac-00000010) |


*Table: This table summarizes the NR2F1 variant classes reported for Bosch–Boonstra–Schaaf optic atrophy syndrome / NR2F1-related neurodevelopmental disorder and the main genotype–phenotype patterns supported by the retrieved literature. It is useful for linking variant location to disease severity, especially ocular and neurodevelopmental features.*