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| Gene | VHL |
| Variant | L188V |
| Impact List | missense |
| Protein Effect | loss of function - predicted |
| Gene Variant Descriptions | VHL L188V does not lie within any known functional domains of the Vhl protein (UniProt.org). L188V demonstrates similar regulation of HIF-alpha, Glut1, and cyclin D1 to wild-type Vhl (PMID: 16452184, PMID: 17526729, PMID: 11331612), and has been demonstrated to both promote (PMID: 16452184) and suppress (PMID: 11331612) tumor formation; however, results in disrupted fibronectin matrix assembly (PMID: 11331612, PMID: 16452184) and elevated Rwdd3 (Rsume), Prkcz (aPKC), and Junb levels in cultured cells (PMID: 16098468, PMID: 30890701), and increased tumor vascularization compared to controls in mouse models (PMID: 16452184), and therefore, is predicted to lead to a loss of Vhl protein function. |
| Associated Drug Resistance | |
| Category Variants Paths |
VHL mutant VHL inact mut VHL L188V |
| Transcript | NM_000551.4 |
| gDNA | chr3:g.10149885C>G |
| cDNA | c.562C>G |
| Protein | p.L188V |
| Source Database | RefSeq |
| Genome Build | GRCh38/hg38 |
| Transcript | gDNA | cDNA | Protein | Source Database | Genome Build |
|---|---|---|---|---|---|
| NM_000551.4 | chr3:g.10149885C>G | c.562C>G | p.L188V | RefSeq | GRCh38/hg38 |
| NM_000551 | chr3:g.10149885C>G | c.562C>G | p.L188V | RefSeq | GRCh38/hg38 |
| NM_000551.3 | chr3:g.10149885C>G | c.562C>G | p.L188V | RefSeq | GRCh38/hg38 |
| Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|
| VHL inact mut | renal cell carcinoma | predicted - sensitive | Alpha 2 Interferon + Bevacizumab | Clinical Study - Cohort | Actionable | In a retrospective analysis, VHL alterations did not impact overall survival or objective response in renal cell carcinoma patients treated with a VEGF-targeted therapy, including Avastin (bevacizumab) and Alpha 2 Interferon combination therapy, but were associated with a prolonged time to progression (PMID: 16827904). | 16827904 |
| VHL inact mut | retinal hemangioblastoma | sensitive | Belzutifan | Phase II | Actionable | In a Phase II trial, Welireg (belzutifan) treatment was safe and resulted in an overall response rate of 32% (16/50, 1 complete response, 15 partial responses) in patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma harboring germline VHL mutations, 69% (11/16) of patients with retinal hemangioblastoma experienced improvement (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). | detail... |
| VHL inact mut | clear cell renal cell carcinoma | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in VHL result in von Hippel-Lindau (VHL) syndrome, which is associated with increased risk of developing clear cell renal cell carcinoma (NCCN.org). | detail... |
| VHL inact mut | hemangioblastoma | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma that do not require immediate surgery (NCCN.org). | detail... |
| VHL inact mut | hemangioblastoma | sensitive | Belzutifan | FDA approved | Actionable | In a Phase II trial (LITESPARK-004) that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in an objective response rate of 44% (22/61, 4 complete responses, 18 partial responses) in patients with Von Hippel-Lindau disease-associated CNS hemangioblastoma harboring germline VHL mutations, with a disease control rate of 90%, a median time to response of 5.4 months, and median progression-free survival not reached (J Clin Oncol 41, 2023 (suppl 16; abstr 2008); NCT03401788). | detail... detail... |
| VHL inact mut | renal cell carcinoma | sensitive | Pazopanib | Guideline | Actionable | Votrient (pazopanib) is included in guidelines as systemic therapy for patients with renal cell carcinoma associated with Von Hippel-Lindau disease (NCCN.org). | detail... |
| VHL inact mut | renal cell carcinoma | sensitive | Pazopanib | Phase II | Actionable | In a Phase II trial, Votrient (pazopanib) treatment resulted in an objective response rate of 42% (13/31, 13 partial responses) and stable disease in 58% of patients with Von Hippel-Lindau disease, with 75% (24/32) of the patients harboring confirmed VHL mutations; 52% (31/59, 2 complete and 29 partial responses) of target renal cell carcinomas responded to the treatment (PMID: 30236511; NCT01436227). | 30236511 |
| VHL inact mut | pancreatic endocrine carcinoma | sensitive | Belzutifan | FDA approved | Actionable | In a Phase II trial that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in an overall response rate of 80% (16/20, 1 complete response, 15 partial responses) in patients with Von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors harboring germline VHL mutations (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). | detail... detail... |
| VHL inact mut | renal cell carcinoma | predicted - sensitive | Everolimus | Case Reports/Case Series | Actionable | In a retrospective analysis from a Phase II clinical trial, patients with metastatic renal cell carcinoma treated with Afinitor (everolimus) had a trend towards improved in progression-free survival when stratified by the presence (median PFS=8.6 months, n=15) or absence (median PFS=5.5 months, n=16) of deleterious VHL mutations (PMID: 26951309). | 26951309 |
| VHL inact mut | renal cell carcinoma | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with localized Von Hippel-Lindau disease-associated renal cell carcinoma harboring germline VHL mutations (PMID: 38788900; ESMO.org). | detail... 38788900 |
| VHL inact mut | renal cell carcinoma | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with Von Hippel-Lindau disease-associated renal cell carcinoma that do not require immediate surgery (NCCN.org). | detail... |
| VHL inact mut | renal cell carcinoma | sensitive | Belzutifan | FDA approved | Actionable | In a Phase II trial that supported FDA approval, Welireg (belzutifan) treatment was safe and resulted in a confirmed partial response (PR) in 36% (22/61) and unconfirmed PR in 11% (7/61) of patients with Von Hippel-Lindau disease-associated localized renal cell carcinoma harboring germline VHL mutations, median duration of response was not reached in responders (J Clin Oncol 39, no. 15_suppl (May 20, 2021) 4555-4555; NCT03401788). | detail... detail... |
| VHL inact mut | islet cell tumor | not applicable | N/A | Guideline | Risk Factor | Germline inactivating mutations in VHL result in von Hippel-Lindau (VHL) syndrome, which is associated with increased risk of developing pancreatic neuroendocrine tumors (NCCN.org). | detail... |
| VHL inact mut | clear cell renal cell carcinoma | conflicting | PT2399 | Preclinical - Pdx | Actionable | In a preclinical study, PT2399 had variable impact on tumor growth in clear cell renal cell carcinoma (ccRCC) cell line and patient-derived xenograft (PDX) models with defective VHL, with decreased tumor growth in a VHL-defective ccRCC PDX model and some VHL-defective ccRCC cell line xenograft models, and no tumor suppression in other cell line xenograft models (PMID: 27595393). | 27595393 |
| VHL inact mut | renal cell carcinoma | no benefit | Apitolisib | Case Reports/Case Series | Actionable | In a retrospective analysis from a Phase II clinical trial, patients with metastatic renal cell carcinoma treated with Apitolisib (GDC-0980) had no difference in progression-free survival when stratified by the presence (n=5) or absence (n=17) of deleterious VHL mutations (PMID: 26951309). | 26951309 |
| VHL mutant | renal cell carcinoma | predicted - sensitive | Sunitinib | Phase I | Actionable | In a Phase I trial, 33% (6/18) of renal cell carcinoma patients harboring a VHL mutation, as determined from archived patient specimens, demonstrated a partial response when treated with Sutent (sunitinib) (PMID: 22105611). | 22105611 |
| VHL mutant | renal cell carcinoma | sensitive | Everolimus | Phase I | Actionable | In a Phase I study, Afinitor (everolimus), as compared to Apitolisib (GDC-0980), resulted in a greater progression free survival and overall survival in patients with renal cell carcinoma harboring VHL mutations (J Clin Oncol 32:5s, 2014 (suppl; abstr 4525)). | detail... |
| VHL mutant | islet cell tumor | sensitive | Belzutifan | Guideline | Actionable | Welireg (belzutifan) is included in guidelines for patients with well-differentiated Grade 1/2 progressive pancreatic neuroendocrine tumors harboring germline VHL mutations (NCCN.org). | detail... |
| VHL mutant | renal cell carcinoma | no benefit | Unspecified VEGFR inhibitor | Clinical Study - Meta-analysis | Actionable | In a meta-analysis of 6 clinical studies, VHL mutation status was not associated with overall response rate (relative risk=1.47, p=0.20), progression-free survival (HR=1.02, p=0.91), or overall survival (HR=0.80, p=0.21) in a total of 633 patients with renal cell carcinoma who received anti-VEGF therapies (PMID: 28103578). | 28103578 |