Table 2.
Variants Identified in MC4R or Lipodystrophy Genes in Participants of European Ancestry
| Gene | Variant | Protein Change | Study MAF | Global Gnomad MAF | Known Functional Annotation | Carrier BMI (mBMI) | Carrier Twin BMI (mBMI) | Non-carrier Twin BMI (mBMI) | Twin Zygo-sity |
|---|---|---|---|---|---|---|---|---|---|
| Obesity | |||||||||
| MC4R | chr18:60371541 G/A | p.Ser270Phe | 0.04% | 0.00% | none | 25.7 (26.1) | 24.8 (24.7) | N/A | MZ |
| MC4R | chr18:60372307 G/A | p.Leu15Phe | 0.04% | 0.00% | none | 23 (22.6) | 22.6 (22.4) | N/A | MZ |
| MC4R | chr18:60371474 CA/C | p.Met292fs | 0.04% | <0.003% | (complete LOF)b | 32.8 (26) | N/A | 28.8 (24.3) | DZ |
| MC4R | chr18:60371644 G/A | p.Arg236Cys | 0.04% | 0.00% | HGMD highC DM (not LOF)b | 34.5 (32.3) | 30 (27.5) | N/A | DZ |
| MC4R | chr18:60372319 T/C | p.Thr11Ala | 0.04% | <0.003% | HGMD lowC DM (not LOF)b | 36 (31.7) | N/A | N/A | N/A |
| MC4R | chr18:60371812 A/G | p.Ser180Pro | 0.04% | <0.003% | ClinVar LP (partial LOF)b | 34.2 (30.2) | 34.4 (33.5) | N/A | DZ |
| MC4R | chr18:60371827 C/T | p.Ala175Thr | 0.04% | 0.02% | ClinVar P HGMD highC DM (partial LOF)b | 29 (25.6) | 28.5 (24.4) | N/A | MZ |
| MC4R | chr18:60371842 T/C | p.Ile170Val | 0.04% | 0.01% | ClinVar P HGMD highC DM (partial LOF)b | 22.6 (23.7) | N/A | 21.3 (24.7) | DZ |
| Lipodystrophy | |||||||||
| ZMPSTE24 | chr1:40290870 G/GT | p.Leu362fs | 0.11% | 0.03% | ClinVar P | 18 (18.9) | N/A | N/A | N/A |
| ZMPSTE24 | chr1:40290870 G/GT | p.Leu362fs | 0.11% | 0.03% | ClinVar P | 22 (20.3) | N/A | N/A | N/A |
| ZMPSTE24 | chr1:40290870 G/GT | p.Leu362fs | 0.11% | 0.03% | ClinVar P | 22.4 (26.1) | N/A | 22.6 (25.1) | DZ |
| ZMPSTE24 | chr1:40290870 GT/G | p.Leu362fs | 0.04% | <0.003% | not annotateda | 30.7 (27.5) | N/A | 24.9 (24.1) | DZ |
| AGPAT2 | chr9:136673876 G/C | p.Ala238Gly | 0.04% | 0.00% | HGMD highC DM | 20 (23.3) | N/A | N/A | N/A |
| LIPE | chr19:42401821 CCCCCCGCAGCCC CCGTCTA/C | p.Val1068fs | 0.04% | 0.07% | ClinVar P | 23 (27.4) | N/A | N/A | N/A |
| BSCL2 | chr11:62692371 C/T | c.863+5G>A | 0.04% | <0.003% | ClinVar P | 24 (29.9) | N/A | N/A | N/A |
MAF, minor allele frequency; HGMD highC DM, Human Gene Mutation Database high-confidence disease-causing mutation; lowC, low confidence; ClinVar LP, likely pathogenic; P, pathogenic; MZ, monozygotic; DZ, dizygotic. Each variant was only seen once in the unrelated participants of this study. See alignments in Figure S5.
a
This deletion at the same site as a lipodystrophy insertion has not previously been annotated.
b
Functional annotation according to Collet et al. (2017), where LOF = loss of function.