Table 2.
Description of the 31 APOE variants.
| rs Number | cDNA Position (NM_000041.4) | Protein Position (NP_000032.1) | Hyperlipidemia | AF a in the ADH/FCHL Cohort | FREX Total AF a | GnomAD Total AF a | PolyPhen 2 b | SIFT c | Mutation Taster d | CADD e | Provean f | Splice Site Affected g | ACMG (Varsome) h | References |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| rs1038445539 | c.-380A > G | 5’UTR variant | FCHL | 0.017 (2/11,486) | 0 | 0.005 (7/152,092) | na | na | na | 7.106 | na | no | na | |
| - | c.-279G > A | 5’UTR variant | FCHL | 0.009 (1/11,486) | 0 | 0 | na | na | na | 5.676 | na | no | na | |
| - | c.-233G > C | 5’UTR variant | ADH | 0.009 (1/11,486) | 0 | 0 | na | na | na | 10.31 (top 10%) | na | no | na | |
| - | c.-105A > G | 5’UTR variant | FCHL | 0.009 (1/11,486) | 0 | 0 | na | na | DC | 22.7 (top 1%) | na | no | VUS | |
| rs766215051 | c.-81G > A | 5’UTR variant | ADH | 0.009 (1/11,486) | 0 | 0.003 (5/152,130) | na | na | DC | 14.13 (top 10%) | na | no | VUS | |
| rs750782549 | c.-78C > G | 5’UTR variant | ADH, FCHL | 0.026 (3/11,486) i | 0 | 0.001 (2/152,116) | na | na | DC | 14.91 (top 10%) | na | no | VUS | |
| rs770658351 | c.43+11G > A | p.? | ADH | 0.009 (1/11,486) | 0 | 0 | na | na | SNP | 13.12 (top 10%) | na | no | VUS | |
| - | c.44-1G > C | p.? | ADH | 0.009 (1/11,486) | 0 | 0 | na | na | DC | 33 (top 0.1%) | na | Yes | P | |
| rs144354013 | c.31A > G | p.Thr11Ala | FCHL | 0.009 (1/11,486) | 0 | 0.009 (13/151,914) | B | T | SNP | 0.294 | N (0.8) | no | VUS/P | |
| rs776242156 | c.68C > T | p.Ala23Val | ADH | 0.009 (1/11,486) | 0 | 0.001 (1/152,206) | B | T | SNP | 0.047 | N (−0.2) | no | VUS/LP | |
| rs111833428 | c.69G > A | p.Ala23= | FCHL | 0.009 (1/11,486) | 0 | 0.023 (35/152,212) | na | na | SNP | 5.195 | N (0) | no | LB | |
| rs769452 | c.137T > C | p.Leu46Pro | ADH, FCHL | 0.157 (18/11,486) | 0.174 (2/1148) | 0.193 (293/152,188) | P | T | DC | 0.72 | N (−1.1) | no | LB | [10] |
| rs767980905 | c.249C > T | p.Asp83= | ADH | 0.009 (1/11,486) | 0 | 0.003 (4/152,218) | na | na | DC | 0.615 | N (0) | no | LB | |
| rs11083750 | c.305C > T | p.Pro102Leu | ADH | 0.009 (1/11,486) | 0 | 0 | PD | D | DC | 23.4 (top 1%) | D (−8.7) | no | LP | |
| rs573658040 | c.409C > T | p.Arg137Cys | ADH | 0.009 (1/11,486) | 0 | 0.002 (3/152,132) | PD | T | DC | 25.8 (top 1%) | N (−2.4) | no | VUS/P | |
| rs11542035 | c.410G > A | p.Arg137His | ADH | 0.009 (1/11,486) | 0 | 0.003(5/152,112) | P | T | SNP | 22.1 (top 1%) | N (−1.0) | no | VUS/P | |
| rs267606664 | c.434G > A | p.Gly145Asp | FCHL | 0.017 (2/11,486) | 0.087 (1/1148) | 0.015 (22/152,152) | PD | T | DC | 24.5 (top 1%) | N (0.656) | no | VUS/P | [27] |
| rs1018669382 | c.463 C > T | p.Leu155Phe | ADH | 0.009 (1/11,486) i | 0 | 0.001 (2/152,148) | B | T | SNP | 5.538 | N (−1.6) | no | VUS/P | |
| rs769455 | c.487C > T | p.Arg163Cys | ADH, FCHL | 0.026 (3/11,486) j | 0 | 0.643 (978/152,126) | PD | D | DC | 28.4 (top 1%) | D (−4.9) | no | VUS/P | [10] |
| rs515726148 | c.500_502delTCC | p.Leu167del | ADH, FCHL | 0.157 (18/11,486) i | 0 | 0.003 (4/152,132) | na | na | SNP | na | D (−7.4) | no | LP | [9,10,16,28,29,30] |
| rs1239911444 | c.517C > T | p.Leu173= | FCHL | 0.009 (1/11,486) | 0 | 0 | na | na | DC | 7.641 | N (0) | no | LB | |
| rs1421977676 | c.536T > C | p.Val179Ala | FCHL | 0.009 (1/11,486) | 0 | 0 | PD | T | SNP | 23.5 (top 1%) | N (−1.0) | no | VUS/P | |
| rs781722239 | c.555C > T | p.Arg185= | ADH | 0.009 (1/11,486) | 0 | 0.009 (13/151,932) | na | na | SNP | 7.192 | N (0) | no | LB | |
| - | c.638T > A | p.Val213Glu | ADH | 0.009 (1/11,486) | 0 | 0 | P | D | SNP | 11.3 (top 10%) | N (−0.6) | no | VUS/P | |
| rs72654468 | c.651C > T | p.Ala217= | ADH | 0.026 (3/11,486) j | 0.182 (2/1,094) | 0.089 (135/151,926) | na | na | SNP | 6.242 | N (0) | no | LB | |
| - | c.652G > T | p.Gly218Cys | ADH | 0.009 (1/11,486) | 0 | 0 | PD | T | SNP | 6.506 | N (−1.4) | no | VUS/P | |
| rs762906934 | c.745G > A | p.Glu249Lys | FCHL | 0.009 (1/11,486) | 0 | 0.001 (1/152,172) | B | T | SNP | 19.7 (top 10%) | N (−1.4) | no | VUS/P | |
| - | c.754G > A | p.Glu252Lys | FCHL | 0.009 (1/11,486) | 0 | 0 | P | D | SNP | 22.2 (top 1%) | D (−2.9) | no | VUS/P | |
| rs267606661 | c.805C > G | p.Arg269Gly | ADH, FCHL | 0.035 (4/11,486) | 0.087 (1/1148) | 0.030 (46/152,200) | P | D | DC | 23.3 (top 1%) | D (−2.9) | no | VUS/P | [10] |
| rs374329439 | c.*25C > T | 3’UTR variant | ADH, FCHL | 0.017 (2/11,486) | 0 | 0.071 (108/152,194) | na | na | SNP | 5.508 | na | no | VUS | |
| - | c.*36C > G | 3’UTR variant | ADH | 0.009 (1/11,486) | 0 | 0 | na | na | SNP | 6.597 | na | no | VUS |
a AF: allele frequency in % (allele count/number), na: not available. b B: benign; PD: probably damaging; P: possibly damaging. c T: tolerated; D: deleterious. d DC: disease-causing; SNP: single nucleotide polymorphism. e Variant with a score ≥ 20 is predicted to be among the top 1% of the most deleterious substitutions in the human genome; a score ≥ 10, among the top 10%. f Variant with a score ≤ −2.5 is considered ‘deleterious’ (D) and a score ≥ 2.5 is considered “neutral” (N). g Potential effect on splicing assessed with Alamut and Human Splicing Finder; Yes: Loss of intron 2 acceptor site. h P: pathogenic; LP: likely pathogenic; VUS: variant of uncertain significance; LB: likely benign. i AF significantly higher in this ADH/FCHL cohort than in GnomAD total population. j AF significantly lower in the studied cohort than in the GnomAD total population.