Description of variants identified in VHL E1′ and VHL E2 with associated clinical manifestations
| Family no., patient . | Nucleotide variant on allele 1/allele 2 . | Impact on protein . | Year of birth/age at diagnosis . | Sex . | Hb, g/dL . | Ht, % . | Red cells, ×109/L . | EPO, mU/mL . | Phenotype . | Other mutation . |
|---|---|---|---|---|---|---|---|---|---|---|
| F1, II.1 | c.429C>T/c.340+770T>C | VHL p.Asp143Asp/X1 p.Ser179Pro? | 1991/15 y | M | 16.6 | 57 | 6.9 | 163 | Erythrocytosis, kidney ischemic infarct | — |
| F2, II.1 | c.598C>T/c.340+770T>C | VHL p.Arg200Trp/X1 p.Ser179Pro? | 1957/21 y | M | 19.9 | 67 | 22.2 | Erythrocytosis | — | |
| F3, II.1 | c.598C>T/c.340+770T>C | VHL p.Arg200Trp/X1 p.Ser179Pro? | 2003/4 mo | M | 17.9 | 54 | 7.5 | 60 | Erythrocytosis | — |
| F3, II.2 | c.598C>T/c.340+770T>C | VHL p.Arg200Trp/X1 p.Ser179Pro? | 2005/6 mo | M | 14.6 | 45 | Erythrocytosis | — | ||
| F4, II.1 | c.598C>T/c.340+694_711dup | VHL p.Arg200Trp/X1 p.Trp159X? | 1990/7 y | M | 20.6 | 64 | 8.25 | 49.9 | Erythrocytosis, deep vein thrombosis, intracerebral hemorrhage | FV Leiden |
| F5, II.2 | c.430G>A/c.340+694_711dup | VHL p.Gly144Arg/X1 p.Trp159X? | 1975/13 y | M | 16.2 | 60 | 5.9 | Erythrocytosis | — | |
| F6, II.1 | c.492G>T/c.340+574A>T* | VHL p.Gln164His/SA | 2014/6 mo | M | 15.6 | 49 | 6.9 | 1167 | Splenomegaly | — |
| F7 | c.340+816A>C/c.340+816A>C | X1 p.*194Serext*24/X1 p.*194Serext*24 | 7 y | M | 20 | 64 | 8.09 | 33 | Erythrocytosis | — |
| F8 | c.340+617C>G + c.340+648T>C†/WT | X1 p.Leu128Val+ X1 p.Leu138Pro/WT | N | N | N | N | VHL disease | — | ||
| F9, II.1 | c.429C>T/c.429C>T | VHL p.Asp143Asp/VHL p.Asp143Asp | 1997/5 mo | M | 16.2 | 49.3 | 5.2 | 186 | Erythrocytosis | Hb sitia |
| F10, II.1 | c.429C>T/c.429C>T | VHL p.Asp143Asp/VHL p.Asp143Asp | 2002/4.5 y | F | 22.5 | 64-77.4 | 12.6 | 264 | Erythrocytosis, splenomegaly | β thalassemia |
| F11 | c.414A>G/WT | VHL p.Pro138Pro/WT | N | N | N | N | VHL disease | — | ||
| F12 | c.414A>G/WT | VHL p.Pro138Pro/WT | N | N | N | N | VHL disease | — |
| Family no., patient . | Nucleotide variant on allele 1/allele 2 . | Impact on protein . | Year of birth/age at diagnosis . | Sex . | Hb, g/dL . | Ht, % . | Red cells, ×109/L . | EPO, mU/mL . | Phenotype . | Other mutation . |
|---|---|---|---|---|---|---|---|---|---|---|
| F1, II.1 | c.429C>T/c.340+770T>C | VHL p.Asp143Asp/X1 p.Ser179Pro? | 1991/15 y | M | 16.6 | 57 | 6.9 | 163 | Erythrocytosis, kidney ischemic infarct | — |
| F2, II.1 | c.598C>T/c.340+770T>C | VHL p.Arg200Trp/X1 p.Ser179Pro? | 1957/21 y | M | 19.9 | 67 | 22.2 | Erythrocytosis | — | |
| F3, II.1 | c.598C>T/c.340+770T>C | VHL p.Arg200Trp/X1 p.Ser179Pro? | 2003/4 mo | M | 17.9 | 54 | 7.5 | 60 | Erythrocytosis | — |
| F3, II.2 | c.598C>T/c.340+770T>C | VHL p.Arg200Trp/X1 p.Ser179Pro? | 2005/6 mo | M | 14.6 | 45 | Erythrocytosis | — | ||
| F4, II.1 | c.598C>T/c.340+694_711dup | VHL p.Arg200Trp/X1 p.Trp159X? | 1990/7 y | M | 20.6 | 64 | 8.25 | 49.9 | Erythrocytosis, deep vein thrombosis, intracerebral hemorrhage | FV Leiden |
| F5, II.2 | c.430G>A/c.340+694_711dup | VHL p.Gly144Arg/X1 p.Trp159X? | 1975/13 y | M | 16.2 | 60 | 5.9 | Erythrocytosis | — | |
| F6, II.1 | c.492G>T/c.340+574A>T* | VHL p.Gln164His/SA | 2014/6 mo | M | 15.6 | 49 | 6.9 | 1167 | Splenomegaly | — |
| F7 | c.340+816A>C/c.340+816A>C | X1 p.*194Serext*24/X1 p.*194Serext*24 | 7 y | M | 20 | 64 | 8.09 | 33 | Erythrocytosis | — |
| F8 | c.340+617C>G + c.340+648T>C†/WT | X1 p.Leu128Val+ X1 p.Leu138Pro/WT | N | N | N | N | VHL disease | — | ||
| F9, II.1 | c.429C>T/c.429C>T | VHL p.Asp143Asp/VHL p.Asp143Asp | 1997/5 mo | M | 16.2 | 49.3 | 5.2 | 186 | Erythrocytosis | Hb sitia |
| F10, II.1 | c.429C>T/c.429C>T | VHL p.Asp143Asp/VHL p.Asp143Asp | 2002/4.5 y | F | 22.5 | 64-77.4 | 12.6 | 264 | Erythrocytosis, splenomegaly | β thalassemia |
| F11 | c.414A>G/WT | VHL p.Pro138Pro/WT | N | N | N | N | VHL disease | — | ||
| F12 | c.414A>G/WT | VHL p.Pro138Pro/WT | N | N | N | N | VHL disease | — |
The second column indicates the position of the nucleotide variants identified in the VHL gene regarding the current nomenclature (sequence encoded by the VHL E1-E2-E3). The third column indicates the impact either on the VHL protein (for variants located in E1, E2, or E3) or on the potential X1 protein, if encoded by E1-E1′ (for variants located in E1′). Normal values correspond to: Hb: M, 13 to 18 g/dL and F, 12 to 15 g/dL; Ht: M, 40% to 52% and F, 37% to 47%; red cells: M, 4.2 to 5.7 × 109/L and F, 4.2 to 5.2 × 109/L; EPO: 5 to 25 mU/mL.
EPO, erythropoietin; Hb, hemoglobin; Ht, hematocrit; N, normal value.
The nucleotide change was reported as rs982745672 with a global minor allele frequency that corresponds to T = 0.00007/2 (TOPMed).
The nucleotide change was reported as rs73024533 with a global minor allele frequency that corresponds to C = 0.0026/13 (1000 Genomes) and C = 0.0050/147 (TOPMed).