About VHL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
VHL c.241C>T, p.(Pro81Ser)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen VHL VCEP v1.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 4
Pathogenic criteria applied · 3
PS3Supporting
PS3 · supporting
Variant-specific functional data from PMID:23990666 demonstrates that P81S VHL disrupts VBC complex interaction (fails to co-immunoprecipitate TCEB1/Elongin C) and stabilizes HIF1A under normoxia in murine ES cells. P81S teratomas showed 3-fold increased volume, reduced apoptosis, and metabolic reprogramming. However, PMID:19228690 found P81S alone has only mild structural effects with preserved HIF-1α regulation in RCC4 cells, indicating partial or context-dependent functional impact. Two independent publications with direct variant testing support PS3 at supporting strength per VCEP rules.
PM1Supporting
PM1 · supporting
The variant is located at codon 81 in the beta domain of VHL (AA 63-155), a key functional domain. Codons 81 and 82 are direct TCEB1 (Elongin C) binding sites critical for VBC E3 ubiquitin ligase complex formation, as confirmed by structural modeling in PMID:23990666. However, cancerhotspots.org does not flag this residue as a statistically significant hotspot, limiting strength to supporting per VCEP rules (PM1_Supporting: <10 instances at the same AA in cancerhotspots.org). COSMIC reports n=20 somatic occurrences, but the VCEP PM1 rule references cancerhotspots.org specifically.
PP3Supporting
PP3 · supporting
REVEL score 0.678 meets the VHL VCEP PP3 threshold of ≥0.664. This supports a deleterious effect prediction for the missense change p.Pro81Ser.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
gnomAD v4.1 grpmax Filtering AF is 0.00042807 (0.0428%), which exceeds the VHL VCEP BA1 threshold of ≥0.000156 (0.0156%). The variant is present in 566 of 1,605,226 alleles including 1 homozygote. This allele frequency is incompatible with a highly penetrant autosomal dominant disorder. BA1 at stand-alone strength independently classifies this variant as Benign.
BS1Strong
BS1 · strong
gnomAD v4.1 grpmax Filtering AF is 0.00042807 (0.0428%), which exceeds the VHL VCEP BS1 threshold of ≥0.0000156 (0.00156%). The variant is too common in the general population to be a cause of VHL disease. Note: BA1 is also met at stand-alone level, which independently establishes benign classification.
BP4Supporting
BP4 · supporting
SpliceAI max delta score is 0.00 (≤0.1), indicating no predicted splicing impact. Per VHL VCEP, BP4 can be applied to assess lack of splicing impact with SpliceAI ≤0.1. Missense predictors are explicitly excluded from BP4 per VCEP rules.
BP6Supporting
BP6 · supporting
Expert panel ClinGen VHL Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Benign
ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1.0 v1.1.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: PS3 supporting, PM1 supporting, PP3 supporting, BA1 stand-alone benign, BS1 strong benign, BP4 supporting benign, BP6 supporting benign; maps to Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
566 / 1,605,226 alleles
gnomAD v4.1: 566 / 1,605,226 alleles. Recorded AF 0.000352598. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000217947; MAF= 0.02179%, 57/261532 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000443589; MAF= 0.04436%, 53/119480 alleles, homozygotes = 0); grpmax FAF= 0.0003518.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0003800629818655663, 7/18418 alleles, homozygotes = 0).
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
22 reported laboratory submissions
10 Uncertain significance · 7 Likely benign · 3 Benign · 1 Likely Benign · 1 likely benign. ClinVar API review status: reviewed by expert panel.
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. VHL, an E3 ubiquitin ligase, is frequently mutated in renal cell carcinomas.
COSMIC
Cancer Hotspots
Somatic evidence
20 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV56546019, n = 20 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen VHL VCEP v1.1.0, with the data and sources behind each one.
27 criteria with recorded statuses: 7 met · 12 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000551.3:c.241C>T (p.Pro81Ser) is present in gnomAD v4.1 at an allele frequency of 0.035% (566/1,605,226 alleles, 1 homozygote) with a GroupMax Filtering AF of 0.0428%, exceeding the VHL VCEP BA1 stand-alone benign threshold of 0.0156%.
BA1 is met at stand-alone strength, independently establishing this variant as Benign per ACMG/AMP 2015 framework and VHL VCEP specifications. This is concordant with the ClinGen VHL Variant Curation Expert Panel classification of Benign (ClinVar VariationID 2233).
The variant also meets BS1 at strong benign strength (grpmax FAF 0.0428% ≥ 0.00156% threshold) and BP4 at supporting benign strength (SpliceAI delta 0.00, no predicted splicing impact).
Pathogenic criteria met at supporting strength only: PS3_Supporting (functional data from PMID:23990666 showing VBC complex disruption and HIF1A stabilization; tempered by mild effects in PMID:19228690), PM1_Supporting (located in beta domain at TCEB1/Elongin C binding site), and PP3 (REVEL 0.678 ≥ 0.664). These are insufficient to offset BA1 stand-alone benign evidence.
This variant has been observed in COSMIC (n=20 somatic occurrences) and is reported in the literature as a trichloroethylene-associated somatic hotspot in clear cell renal cell carcinoma, but somatic mutation frequency does not alter the germline classification.
No criteria match.
Met · 7
PS3 SupportingVariant-specific functional data from PMID:23990666 demonstrates that P81S VHL disrupts VBC complex interaction (fails to co-immunoprecipitate TCEB1/Elongin C) and stabilizes HIF1A under normoxia in murine ES cells. P81S teratomas showed 3-fold increased volume, reduced apoptosis, and metabolic reprogramming. However, PMID:19228690 found P81S alone has only mild structural effects with preserved HIF-1α regulation in RCC4 cells, indicating partial or context-dependent functional impact. Two independent publications with direct variant testing support PS3 at supporting strength per VCEP rules. Details ▾Hide ▴
Evidence considered
- PMID:23990666: P81S disrupts VBC complex (loss of Elongin C co-IP)
- stabilizes HIF1A under normoxia
- alters metabolic programming
- reduces apoptosis in teratoma model.
- PMID:19228690: P81S alone in RCC4 cells shows normal HIF-1α regulation and preserved CBC-VHL complex in vivo
- mild VCB instability at 37°C in vitro.
- VCEP PS3 rule: HIF1/2a degradation assay and VBC complex stability are acceptable functional readouts
- proposed strength PS3_Supporting.
Still missing
- Functional data from PMID:23990666 is in somatic/TCE-exposure context
- germline-specific functional characterization not available.
- Conflicting mild vs. moderate effect between the two studies.
Sources
PM1 SupportingThe variant is located at codon 81 in the beta domain of VHL (AA 63-155), a key functional domain. Codons 81 and 82 are direct TCEB1 (Elongin C) binding sites critical for VBC E3 ubiquitin ligase complex formation, as confirmed by structural modeling in PMID:23990666. However, cancerhotspots.org does not flag this residue as a statistically significant hotspot, limiting strength to supporting per VCEP rules (PM1_Supporting: <10 instances at the same AA in cancerhotspots.org). COSMIC reports n=20 somatic occurrences, but the VCEP PM1 rule references cancerhotspots.org specifically. Details ▾Hide ▴
Evidence considered
- Position 81 is a direct TCEB1/Elongin C binding site in the VHL beta domain.
- COSMIC: n=20 somatic occurrences (COSV56546019).
- cancerhotspots.org: not a statistically significant hotspot.
- VCEP PM1: key functional domain qualifies
- Supporting strength for <10 cancerhotspots.org instances.
Still missing
- VHL VCEP germline hotspot table not directly accessible for confirmation of germline hotspot status.
Sources
PP3 SupportingREVEL score 0.678 meets the VHL VCEP PP3 threshold of ≥0.664. This supports a deleterious effect prediction for the missense change p.Pro81Ser. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.678 (local lookup chr3:10142088 C>T).
- VCEP PP3 threshold: REVEL ≥ 0.664.
- SpliceAI max delta: 0.00 (no predicted splicing impact).
Sources
revelcspec ↗
BA1 Stand alonegnomAD v4.1 grpmax Filtering AF is 0.00042807 (0.0428%), which exceeds the VHL VCEP BA1 threshold of ≥0.000156 (0.0156%). The variant is present in 566 of 1,605,226 alleles including 1 homozygote. This allele frequency is incompatible with a highly penetrant autosomal dominant disorder. BA1 at stand-alone strength independently classifies this variant as Benign. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF 0.000352598 (566/1
- 605
- 226 alleles)
- grpmax FAF 0.00042807.
- 1 homozygote present in gnomAD v4.
- VCEP BA1 threshold: ≥0.000156 (0.0156%) GroupMax FAF.
- 0.00042807 ≥ 0.000156 → BA1 met at Stand Alone.
Sources
BS1 StronggnomAD v4.1 grpmax Filtering AF is 0.00042807 (0.0428%), which exceeds the VHL VCEP BS1 threshold of ≥0.0000156 (0.00156%). The variant is too common in the general population to be a cause of VHL disease. Note: BA1 is also met at stand-alone level, which independently establishes benign classification. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: grpmax FAF 0.00042807.
- VCEP BS1 threshold: ≥0.0000156.
- 0.00042807 ≥ 0.0000156 → BS1 met at Strong.
Sources
BP4 SupportingSpliceAI max delta score is 0.00 (≤0.1), indicating no predicted splicing impact. Per VHL VCEP, BP4 can be applied to assess lack of splicing impact with SpliceAI ≤0.1. Missense predictors are explicitly excluded from BP4 per VCEP rules. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00 (no predicted splice impact).
- VCEP BP4: SpliceAI ≤0.1 indicates lack of splicing impact.
- REVEL and BayesDel not used per VCEP exclusion of missense predictors for BP4.
Still missing
- VarSeak score not available for concordance confirmation per VCEP recommendation.
Sources
Not met · 12 · evaluated, threshold not reached
PS1 No different nucleotide change resulting in the same amino acid substitution (p.Pro81Ser) has been established as pathogenic under VHL VCEP specifications. This exact variant (c.241C>T) has been classified as Benign by the ClinGen VHL Expert Panel, so PS1 does not apply. Details ▾Hide ▴
PS2 No de novo observation data available for this variant. No proband with confirmed maternity and paternity testing identified in the literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No de novo reports in 29 ClinVar submissions.
Still missing
- No de novo testing data available.
Sources
PS4 No proband counting or case-control data available to apply the VHL VCEP PS4 point scoring system. The variant's presence in gnomAD at grpmax FAF 0.0428% (566 alleles, 1 homozygote) argues against significant enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 566/1
- 605
- 226 alleles (AF 0.035%)
- 1 homozygote.
- Expert panel classification of Benign is inconsistent with PS4 enrichment.
Still missing
- No proband counting data from case series.
- No formal case-control comparison.
Sources
PM2 gnomAD v4.1 grpmax Filtering AF is 0.00042807 (0.0428%), which exceeds the VHL VCEP PM2_Supporting threshold of ≤0.00000156 (0.000156%). The variant is present in 566 alleles including 1 homozygote in gnomAD v4. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 566/1
- 605
- 226 alleles
- grpmax FAF 0.00042807.
- VCEP PM2_Supporting threshold: ≤0.00000156.
- 0.00042807 > 0.00000156 → PM2 not met.
Sources
PM5 No different pathogenic missense variant at the same amino acid residue (P81) has been identified that is classified under VHL VCEP specifications. The PM5 candidate search returned no eligible comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found no same-residue pathogenic missense comparators.
- VCEP PM5 rule requires prior variant pathogenicity established by VHL VCEP.
Sources
pm5_candidatescspec ↗
PM6 No de novo observation data (assumed or confirmed) available for this variant. No proband reports in ClinVar submissions or literature indicating de novo occurrence. Details ▾Hide ▴
Evidence considered
- No de novo reports in any of 29 ClinVar submissions.
Still missing
- No parental testing data available.
Sources
PP1 No co-segregation data available for this variant. No family studies with meioses counts identified in the literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No segregation analysis data found in any reviewed source.
Still missing
- No family-based segregation studies available.
BS2 Although gnomAD v4 contains 1 homozygote for this variant, no phenotype or age data are available for this individual. The VHL VCEP requires at least 3 individuals ≥65 years, unaffected, with full phenotyping and screening (BS2_Strong) or lacking full phenotyping (BS2_Supporting). This threshold is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4: 1 homozygote identified but no phenotype data.
- VCEP BS2 requires ≥3 individuals ≥65yo
- unaffected.
Still missing
- No phenotype or age data for gnomAD homozygote.
- No systematically collected unaffected elderly control data.
Sources
BS3 Functional data is conflicting. PMID:23990666 shows P81S disrupts VBC complex interactions and stabilizes HIF1A (supporting a damaging effect), while PMID:19228690 shows that P81S alone preserves near-normal HIF-1α regulation in RCC4 cells with only mild structural perturbation. Net evidence does not clearly demonstrate no damaging effect on protein function, which is required for BS3. Details ▾Hide ▴
Evidence considered
- PMID:23990666: P81S disrupts VBC
- stabilizes HIF1A (damaging).
- PMID:19228690: P81S alone preserves HIF-1α regulation
- mild VCB instability at 37°C only.
- Conflicting evidence precludes BS3 application.
Still missing
- No consensus functional study specifically designed to resolve conflicting findings.
- No fibronectin/ECM functional data for P81S specifically.
Sources
BS4 No lack-of-segregation data available. The VHL VCEP requires observation of lack of segregation in affected members of ≥1 family for BS4_Supporting or ≥2 families for BS4_Strong. No such data were identified. Details ▾Hide ▴
Evidence considered
- No segregation data found in any reviewed source.
Still missing
- No family-based segregation studies available.
BP2 No evidence of this variant observed in trans with a known pathogenic VHL variant, in homozygous state with phenotype data, or in cis with multiple pathogenic VHL variants. The gnomAD homozygote lacks clinical phenotype data. Details ▾Hide ▴
Evidence considered
- gnomAD v4 homozygote lacks clinical annotation.
- No phase-confirmed trans/cis data available.
Still missing
- No phase data with pathogenic VHL variants.
- No phenotype data for gnomAD homozygote.
Sources
BP5 No evidence of co-occurrence with a pathogenic variant in a different gene that fully explains the patient's phenotype, per VHL VCEP BP5 requirements. Details ▾Hide ▴
Evidence considered
- No co-occurrence data found in any reviewed source.
Still missing
- No co-occurrence case data available.
Not assessed · 1 · no assessment recorded
PS5 PS5 is a deprecated ACMG criterion; not part of the active VHL VCEP framework. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000551.3:c.241C>T is a missense variant (p.Pro81Ser). PVS1 applies only to null variants (nonsense, frameshift, canonical splice site ±1,2). Per VHL VCEP, PVS1 is reserved for truncating variants after Met54 predicted to undergo NMD, or canonical splice disruptions. Details ▾Hide ▴
Evidence considered
- Missense substitution does not fall into PVS1 null-variant buckets.
- pvs1_variant_assessment confirms variant bucket = 'other'
- generic PVS1 framework not applicable.
Sources
PP2 VCEPPer VHL VCEP: PP2 is not applicable. VHL is not intolerant to missense variation (gnomAD Z score = -0.39), and there is evidence of benign/common missense variants in VHL. Details ▾Hide ▴
Evidence considered
- VCEP states: 'Do not use. While there are known pathogenic missense in VHL
- there is also evidence of benign or common missense in VHL.'
Sources
PP4 VCEPPer VHL VCEP: PP4 is not applicable. The VCEP directs combining phenotype specificity assessment with PS4 to avoid double-counting probands. Details ▾Hide ▴
Evidence considered
- VCEP PP4: 'Not applicable — Combine with PS4 to avoid double counting probands.'
Sources
PP5 VCEPPer VHL VCEP: PP5 is not applicable. The ClinGen Sequence Variant Interpretation VCEP Review Committee recommends against use of this criterion. Details ▾Hide ▴
BP1 VCEPPer VHL VCEP: BP1 is not applicable. Truncating variants account for only a portion of disease-causing variants in VHL; missense variants are a common mechanism of disease. Details ▾Hide ▴
Evidence considered
- VCEP BP1: 'This rule code does not apply to this gene
- as truncating variants account for only a portion of disease-causing variants.'
Sources
BP3 N/AIn-frame insertions/deletions in repetitive regions. This is a missense substitution; not applicable per VCEP (BP3 applies only to the 8x GXEEX repeat motif at AA14-AA48 in VHL p30). Details ▾Hide ▴
No further detail was recorded.
BP7 N/AMissense variant. Per VHL VCEP, BP7 applies only to silent or intronic variants where BP4 is met for lack of splice effect and PhyloP ≤0.2. Details ▾Hide ▴
Evidence considered
- Variant is missense (c.241C>T
- p.Pro81Ser)
- BP7 is for silent/intronic variants only.
Sources
Identifiers
- Gene
- VHL
- Transcript
- NM_000551.3
- Coding (HGVS c.)
- NM_000551.3:c.241C>T
- Protein (HGVS p.)
- NP_000542.1:p.(Pro81Ser)
- GRCh38
- chr3:10142088 C>T
- GRCh37
- chr3:10183772 C>T
- ClinVar
- 2233
- COSMIC
- COSV56546019
Gene diagram
Every interpreted variant in VHL, mapped onto the exon structure of NM_000551.3. Select a row to find it on the plot.
VHLNM_000551.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in VHL
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
566 / 1,605,226 alleles
AF 0.000353 · 1 homozygotes · FAF 0.000428
gnomAD v2.1
57 / 261,532 alleles
AF 0.000218 · 0 homozygotes · FAF 0.000352
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00035 · 566 / 1,605,226 alleles · 1 hom · FAF 0.00043
| European (non-Finnish)543 / 1,179,690 | 0.000461 hom |
| Remaining individuals9 / 62,362 | 0.00014 |
| African/African American7 / 74,924 | 9.3e-05 |
| Admixed American4 / 59,932 | 6.7e-05 |
| European (Finnish)2 / 55,888 | 3.6e-05 |
| South Asian1 / 91,022 | 1.1e-05 |
0 alternate alleles recorded in 4 other groups: Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00022 · 57 / 261,532 alleles · 0 hom · FAF 0.00035
| European (non-Finnish)53 / 119,480 | 0.00044 |
| Remaining individuals1 / 6,852 | 0.00015 |
| African/African American2 / 22,676 | 8.8e-05 |
| Admixed American1 / 34,870 | 2.9e-05 |
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000352598; MAF= 0.03526%, 566/1605226 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00046029; MAF= 0.04603%, 543/1179690 alleles, homozygotes = 1); grpmax FAF= 0.00042807.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000217947; MAF= 0.02179%, 57/261532 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000443589; MAF= 0.04436%, 53/119480 alleles, homozygotes = 0); grpmax FAF= 0.0003518.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0003800629818655663, 7/18418 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.678
- BayesDel
- 0.207
How the predictions were used
PP3 SupportingREVEL score 0.678 meets the VHL VCEP PP3 threshold of ≥0.664. This supports a deleterious effect prediction for the missense change p.Pro81Ser. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.678 (local lookup chr3:10142088 C>T).
- VCEP PP3 threshold: REVEL ≥ 0.664.
- SpliceAI max delta: 0.00 (no predicted splicing impact).
Sources
revelcspec ↗
BP4 SupportingSpliceAI max delta score is 0.00 (≤0.1), indicating no predicted splicing impact. Per VHL VCEP, BP4 can be applied to assess lack of splicing impact with SpliceAI ≤0.1. Missense predictors are explicitly excluded from BP4 per VCEP rules. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00 (no predicted splice impact).
- VCEP BP4: SpliceAI ≤0.1 indicates lack of splicing impact.
- REVEL and BayesDel not used per VCEP exclusion of missense predictors for BP4.
Still missing
- VarSeak score not available for concordance confirmation per VCEP recommendation.
Sources
BP7 N/AMissense variant. Per VHL VCEP, BP7 applies only to silent or intronic variants where BP4 is met for lack of splice effect and PhyloP ≤0.2. Details ▾Hide ▴
Evidence considered
- Variant is missense (c.241C>T
- p.Pro81Ser)
- BP7 is for silent/intronic variants only.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.678. BayesDel score = 0.207126.
7 paper records listed. 2 cited in the classification.
Cited in the classification
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PMID 19228690 ↗VHL mutations linked to type 2C von Hippel-Lindau disease cause extensive structural perturbations in pVHL.Structural and biochemical analysis of type 2C VHL disease-associated pVHL mutants, including P81S alone and P81S/L188V double mutant. P81S single mutant shows only mild effects: HIF-1α binding affinity reduced 3-fold (Kd 15.8 vs 5.7 nM WT), slight VCB complex instability at 37°C, and near-normal NMR spectrum. In RCC4 cells, P81S alone preserves normal HIF-1α regulation and CBC-VHL complex stability. P81S/L188V double mutant shows more severe structural perturbations. Authors note P81S single mutation has been linked to low-penetrance type 1 VHL disease.→ PS3 Names this variant
Source detail
The P81S single mutation, in turn, has been linked to low penetrance type 1 von Hippel-Lindau disease (36) and, in combination with additional VHL mutations, to sporadic, trichloroethylene-induced renal cell carcinomas (37, 38).
Location Introduction (para 5); Table 1; Results 'Type 2C-associated pVHL Mutant Proteins Are Proficient in Substrate Binding'; Figures 1-6
Context Recombinant VCB complexes expressed in E. coli; in vitro translation in reticulocyte lysate; RCC4 VHL-/- renal cell carcinoma cells; 293T cells; NMR spectroscopy; tryptic proteolysis; size exclusion chromatography
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PMID 23990666 ↗Pleiotropic effects of the trichloroethylene-associated P81S VHL mutation on metabolism, apoptosis, and ATM-mediated DNA damage response.Comprehensive functional characterization of the trichloroethylene-associated P81S VHL mutation. P81S disrupts VBC E3 ubiquitin ligase complex interaction (loss of Elongin C/TCEB1 co-immunoprecipitation), stabilizes HIF1A under normoxia, and differentially activates HIF target genes. In murine teratoma models, P81S produced 3-fold larger tumors with reduced apoptosis and suppressed ATM-mediated DNA damage response. Demonstrates P81S confers pleiotropic effects including metabolic reprogramming toward fatty acid oxidation and glutaminolysis.→ PS3 → PM1 Names this variant
Source detail
This mutation results in a single amino acid change from proline to serine at codon 81 of the VHL protein (P81S) and is observed in more than 39% of TCE-exposed individuals who developed ccRCC.
Location Abstract; Results paragraphs 1-6; Figures 1-7
Context Vhl-/- murine ES cells expressing HA-tagged human WT, P81S, or R167Q VHL; teratoma xenografts in Foxn1nu/nu mice; co-immunoprecipitation; Western blot; RT-PCR; microarray
Other recorded publications
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PMID 17102082 ↗Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients.Genetic mutation screening in an Italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients for SDHB, SDHC, SDHD, VHL, and RET mutations. NM_000551.3:c.241C>T (p.Pro81Ser) was not identified in the abstract of this paper.Does not name this variant
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PMID 22241717 ↗Head and neck paragangliomas: genetic spectrum and clinical variability in 79 consecutive patients.Genetic screening study of 79 patients with head and neck paragangliomas for mutations in SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, MAX, and TMEM127. Two VHL germline mutation carriers were identified but the specific VHL variants are not described in the abstract or title. NM_000551.3:c.241C>T (p.Pro81Ser) was not identified in this paper.Does not name this variant
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PMID 24446253 ↗VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma.Study of VHL and HIF-1α gene variations and their prognostic significance in early-stage clear cell renal cell carcinoma. Investigates VHL mutations, methylation, LOH, and HIF-1α C1772T SNP. NM_000551.3:c.241C>T (p.Pro81Ser) was not identified in this paper.Does not name this variant
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PMID 19906784 ↗Pathogenicity of DNA variants and double mutations in multiple endocrine neoplasia type 2 and von Hippel-Lindau syndrome.Study of DNA variants and double mutations in MEN2 and von Hippel-Lindau syndrome. Discusses variant pathogenicity in pheochromocytoma-associated syndromes. NM_000551.3:c.241C>T (p.Pro81Ser) was not identified in the abstract of this paper.Does not name this variant
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.ACMG/AMP standards and guidelines for the interpretation of sequence variants. Provides the generic framework for variant classification but does not discuss any specific variant. NM_000551.3:c.241C>T (p.Pro81Ser) was not identified in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
566 / 1,605,226 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
10 Uncertain significance · 7 Likely benign · 3 Benign · 1 Likely Benign · 1 likely benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/1527855755
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/2233/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-10183772-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-10142088-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-10142088-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000551.3%3Ac.241C…
- OncoKB ↗www.oncokb.org/gene/VHL/P81S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121592646
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000352598; MAF= 0.03526%, 566/1605226 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.00046029; MAF= 0.04603%, 543/1179690 alleles, homozygotes = 1); grpmax FAF= 0.00042807.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000217947; MAF= 0.02179%, 57/261532 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000443589; MAF= 0.04436%, 53/119480 alleles, homozygotes = 0); grpmax FAF= 0.0003518.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0003800629818655663, 7/18418 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Likely benign (7 clinical laboratories) and as Benign (3 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as likely benign (1 clinical laboratory) and as Benign by ClinGen VHL Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 2233)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.678. BayesDel score = 0.207126.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. VHL, an E3 ubiquitin ligase, is frequently mutated in renal cell carcinomas.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56546019, n = 20 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.