Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
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Variant: NM_000551.4(VHL):c.500G>A (p.Arg167Gln)

CA020454

2216 (ClinVar)

Gene: VHL
Condition: von Hippel-Lindau disease
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 4ea45f90-dbaf-4727-8a3b-44b9825cce21
Approved on: 2024-06-25
Published on: 2024-06-25

HGVS expressions

NM_000551.4:c.500G>A
NM_000551.4(VHL):c.500G>A (p.Arg167Gln)
NC_000003.12:g.10149823G>A
CM000665.2:g.10149823G>A
NC_000003.11:g.10191507G>A
CM000665.1:g.10191507G>A
NC_000003.10:g.10166507G>A
NG_008212.3:g.13189G>A
ENST00000696142.1:c.*177G>A
ENST00000696143.1:c.636G>A
ENST00000696153.1:c.611G>A
ENST00000256474.3:c.500G>A
ENST00000256474.2:c.500G>A
ENST00000345392.2:c.377G>A
ENST00000477538.1:n.636G>A
NM_000551.3:c.500G>A
NM_198156.2:c.377G>A
NM_001354723.1:c.*54G>A
NM_001354723.2:c.*54G>A
NM_198156.3:c.377G>A

Pathogenic

Met criteria codes 6
PS3_Supporting PS4 PP3 PM1 PM6 PM2_Supporting
Not Met criteria codes 12
BS2 BS3 BS1 BP5 BP7 PVS1 BP2 BP3 BP4 BA1 PM4 PM5

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
VHL VCEP
The NM_000551.4(VHL):c.500G>A (p.Arg167Gln) variant in VHL is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 167. This missense mutation has been identified in at least 19 unrelated individuals with von Hippel-Lindau disease. Mostly VHL Type 2 or 2B phenotypes are noted. However, some publications describe VHL Type 1 as well. PMIDs used: 20846682, 8707293, 9829912, 9829911, 7728151, 12114495, 12624160, 14722919. CIViC EIDs used (https://civicdb.org): 5485, 5354, 5264, 5062, 4913, 5487, 5546, 6118. 2 participating commercial laboratories reported >7 and >20 cases. The number of proband and/or family cases fulfills the criteria for strong evidence (PS4). Multiple publications (PMID: 15574766, PMID: 19030229) support disruption of Elongin C binding with the Arg167Gln variant, as well as altered regulation of HIF2a and near wild type regulation via ubiquitination of HIF1a (PS3_Supporting). A de novo (and mosaic ~5.5% allele freq in blood and ~34% in a pheochromocytoma at ~80% tumor purity) case was identified in a 16yo with no family history of VHL and fulfilling Danish Criteria for VHL (The 16yo had the following: Hb, pheochromocytoma, pancreatic endocrine tumor, left adrenal nodule). PMID: 30731206, CIViC evidence ID: EID7714. 1 commercial laboratory reports a de novo case in a child with bilateral retinal hemangiomas in the age range of 10yo (PM6). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Arg167 is one of the germline hotspots outlined by the VHL VCEP, and it is in the Elongin binding domain (PM1). The computational predictor REVEL gives a score of 0.874, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). Per VHL VCEP specifications, this code is applied when the REVEL score is >=0.6. (PP3). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024).
Met criteria codes
PS3_Supporting
Multiple publications support disruption of Elongin C binding with the Arg167Gln variant, as well as altered regulation of HIF2a and near wild type regulation via ubiquitination of HIF1a.
Rathmell et al results display R167Q has impaired regulation of HIF2a, normal regulation of HIF1a, and impaired binding to Elongin C. PubMed:15574766
Hacker et al shows R167Q confers partial suppression of HIF2a , inability to bind Elongin C and retains the ability to ubiquitinate HIF1a, similar to WT VHL. PubMed:19030229
PS4
This missense mutation has been identified in >=19 unrelated individuals with Von Hippel Lindau disease. Mostly VHL Type 2 or 2B is noted, however, some describe VHL Type 1 as well. PMIDs used: 20846682, 8707293, 9829912, 9829911, 7728151, 12114495, 12624160, 14722919. CIViC EIDs used: 5485, 5354, 5264, 5062, 4913, 5487, 5546, 6118. 2 participating commercial laboratories reported >7 and >20 cases. The number of proband and/or family cases fulfills the criteria for strong evidence (PS4).
PP3
The computational predictor REVEL gives a score of 0.874, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3).
PM1
Arg167 is one of the germline hotspots outlined by the VHL VCEP.
PM6
A de novo (and mosaic ~5.5% allele freq in blood and ~34% in a pheochromocytoma at ~80% tumor purity) case was identified in a 16yo with no family history of VHL and fulfilling Danish Criteria for VHL (The 16yo had the following: Hb, pheochromocytoma, pancreatic endocrine tumor, left adrenal nodule). PMID: 30731206, CIViC evidence ID: EID7714. 1 commercial laboratory reports a de novo case in a child with bilateral retinal hemangiomas in the age range of 10yo.
PM2_Supporting
This variant is absent from gnomAD v4.1.0 (PM2_Supporting).
Not Met criteria codes
BS2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP5
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP7
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PVS1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BP4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM4
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM5
The Arg167Trp variant is interpreted as pathogenic according to several groups, but has not been interpreted by the VHL VCEP specifications, therefor this code is not met.
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