Table 2:
Disease-associated alleles reported to date
| Varianta | gnomAD allele frequency | In silico predictionsb | Protein domainc | ACMG classificationd | Reference |
|---|---|---|---|---|---|
| c.170delG, p.(Gly57Glufs*12) | 2.48e-5 | Disease causing | RCC1 | Pathogenic (PVS1, PM2, PP1-M) | Huang et al.(3); Yang et al.(4) |
| c.358C>T, p.(Gln120*) | Absent | Disease causing | RCC2 | Likely Pathogenic (PVS1, PM2) | Current manuscript |
| c.671C>T, p.(Pro224Leu) | 1.35e-5 | Deleterious; Probably Damaging | RCC4 | VUS (PM1, PM2_supporting, PM3_supporting, PP3) | Current manuscript |
| c.707delA, p.(Asn236Thrfs*11) | 1.2e-4 | Disease causing | RCC4 | Pathogenic (PVS1, PM2, PP1-M) | Huang et al.(3) |
| c.905_906insTT, p.(Gln303Cysfs*17) | Absent | Disease causing | RCC5/6 | Likely Pathogenic (PVS1, PM2) | Yang et al.(4) |
| c.919G>A, p.(Val307Met) | 1.2e-5 | Deleterious; Probably Damaging | RCC6 | Likely Pathogenic (PM1, PM2, PP1-M, PP3) | Coppieters et al.(6) |
| c.930G>T, p.(Trp310Cys) | 7.96e-6 | Deleterious; Probably Damaging | RCC6 | Likely Pathogenic (PM1, PM2, PP1-M, PP3) | Coppieters et al.(6) |
| c.973C>T, p.(His325Tyr) | 1.42e-4 | Tolerated; Possibly Damaging | RCC6 | VUS (PM1, PM2, PP1) | Coppieters et al.(6) |
| c.1025C>T, p.(Ser342Leu) | 1.1e-4 | Tolerated; Benign | RCC6 | Likely Pathogenic (PM1, PM2, PP1-M) | Current manuscript |
| c.1151A>G, p.(His384Arg) | 9.22e-5 | Deleterious; Probably Damaging | BTB1 | Likely Pathogenic (PM1, PM2, PP1, PP3) | Coppieters et al.(6) |
| c.1164G>T, p.(Leu388Phe) | Absent | Deleterious; Benign | BTB1 | Likely Pathogenic (PM1, PM2, PP1, PP3) | Coppieters et al.(6) |
| c.1202C>T, p.(Ser401Leu) | 3.2e-5 | Tolerated; Benign | BTB1 | VUS (PM1, PM2, PP1) | Coppieters et al.(6) |
Variants are based on transcript NM_018191.4
SIFT and PolyPhen-2 predictions are shown for missense variants; MutationTaster predictions are shown for variants that result in premature protein truncation.
RCC: six repeats of RCC1(regulator of chromatin condensation 1)-like domain, BTB:
American College of Medical Genetics (ACMG) variant classification (PVS1:null variant; PM1:variant in a functional domain; PM2: extremely rare; PM3: detected in trans with a pathogenic variant; PP1:variant segregates with disease in multiple affected individuals; PP1-M: same as PP1 with multiple families; PP3: multiple lines of computational evidence support a deleterious effect)
Abbreviations: VUS – variant of uncertain significance