Clinical manifestation of 20 consecutive families with von Hippel-Lindau disease (VHL). Details of germline mutations found in VHL families without (type 1) and with (type 2) phaeochromocytoma
| VHL Family | VHL type | Family history | No | HB | RA | RC | PC | PH | Mutation at nt level of ORFf | Exon | Consequence to pVHLf | Type of mutation | Reference |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| aFurther investigation showed that the mother of the patient was an asymptomatic carrier of the mutation. bOne patient per family with renal tumour <3 cm under follow up detected by imaging. cAlthough we did not observe RC, the germline mutations are described as associated with the VHL type 2B phenotype. dPancreatic cystadenoma. eThe proband presented with one tumour which biopsy showed to be a non-functional paraganglioma. fNomenclature according to Antonarakis et al (1998). gProtein stops at residue 142. hProtein stops at residue 157. iNew at nucleotide level, but already described at aa level. jAllele frequency in normal Brazilian population. | |||||||||||||
| No = number of affected members in each VHL family; HB = haemangioblastoma of CNS; RA = retinal angioma; RC = renal carcinoma; PC = pancreatic carcinoma; PH = phaeochromocytoma; nt = nucleotide; ORF = open reading frame; aa = amino acid; new site = novel germline mutation. | |||||||||||||
| 1 | 1 | Yes | 5 | 4 | – | 2 | – | – | 226-228 del TCT | 1 | delPhe76 | In frame del | 41 |
| 2 | 1 | Yes | 10 | 7 | 3 | 3 | – | – | 238A>C | 1 | Ser80Arg | Missense | Noveli |
| 3 | 1 | Yes | 2 | 1 | 1 | – | – | – | 262T>C | 1 | Trp88Arg | Missense | Noveli |
| 4 | 1 | Yes | 3 | 2 | 3 | – | – | – | 280G>T | 1 | Glu94Stop | Nonsense | 12 |
| 5 | 1 | Yes | 2 | 2 | – | – | – | – | 302T>G | 1 | Leu101Arg | Missesnse | 31 |
| 6 | 1 | No | 1 | 1 | – | 1 | –d | – | 305 del C | 1 | Frameshift at aa 102g | Frameshift | Novel |
| 7 | 1 | Yes | 5 | 4 | 3 | 2 | – | –e | 320G>C | 1 | Arg107Pro | Missense | 33 |
| 8 | 1 | Yes | 2 | 2 | – | – | – | – | IVS1+7G>A | Intron 1 | – | Splicing defect | Novel |
| 9 | 1 | Yes | 3 | 1 | 1 | 1 | – | – | 344 del A | 2 | Frameshift at aa 115h | Frameshift | Novel |
| 10 | 2 | No | 1 | – | 1 | – | – | 1 | 371C>T | 2 | Thr124Ile | Missense | Novel |
| 11 | 1 | Yes | 14 | 7 | 2 | 1 | –d | – | 388G>T | 2 | Val130Phe | Missense | Novel |
| 12 | 1 | Yes | 8 | 7 | 1 | 2b | – | – | 407T>C | 2 | Phe136Ser | Missense | 12 |
| 13 | 1 | Noa | 1 | 1 | 1 | 1b | – | – | 436 del C | 2 | Frameshift at aa 146h | Frameshift | Novel |
| 14 | 1 | Yes | 5 | 3 | 1 | 1 | –d | – | IVS2+1G>A | Intron 2 | – | Splicing defect | 32 |
| 15 | 2 | Yes | 2 | 1 | – | –c | – | 2 | 499C>T | 3 | Arg167Trp | Missense | 12 |
| 16 | 2 | Yes | 4 | 2 | – | –c | – | 3 | 500G>A | 3 | Arg167Gln | Missense | 12 |
| 17 | 1 | Yes | 10 | 10 | 1 | 5b | – | – | Partial deletion | – | Rearrangement | – | |
| 18 | 1 | Yes | 5 | 2 | 1 | – | –d | – | Partial deletion | – | – | Rearrangement | – |
| 19 | 1 | Yes | 3 | 3 | – | – | – | – | Partial deletion | – | – | Rearrangement | – |
| 20 | 1 | Yes | 6 | 4 | – | 3b | 1 | – | Complete deletion | – | – | Rearrangement | – |
| 9, 17 | – | – | – | – | – | – | – | – | 183C>G | 1 | Synonym | Polymorphism | 1.16%j |
| 16 | – | – | – | – | – | – | – | – | IVS2 –95T>A | Intron 2 | Apparently no effect | Polymorphism | 1.69%j |