About VHL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
VHL c.154G>A, p.(Glu52Lys)
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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
VHL VCEP BA1 threshold: GroupMax FAF ≥ 0.000156 (0.0156%) in gnomAD v4. This variant has gnomAD v4 GroupMax FAF = 0.0008611 (0.08611%) in the African/African American population (78/74,388 alleles, 1 homozygote). This is approximately 5.5-fold above the BA1 cutoff. The variant is also observed in gnomAD v2.1 with grpmax FAF 0.00037662 in the same population group. BA1 is met as stand-alone benign evidence, independently sufficient to classify this variant as benign regardless of other criteria.
BS1Strong
BS1 · strong
VHL VCEP BS1 threshold: GroupMax FAF ≥ 0.0000156 (0.00156%) in gnomAD v4. This variant has gnomAD v4 GroupMax FAF = 0.0008611 (0.08611%), which is approximately 55-fold above the BS1 cutoff. BS1 is met as strong benign evidence. Note: BA1 (stand-alone) subsumes BS1; both are independently met.
BP4Supporting
BP4 · supporting
VHL VCEP BP4: missense predictors should not be used for BP4, but BP4 can be applied to assess lack of splicing impact with SpliceAI ≤ 0.1 and VarSeak Class 1 or 2. This variant has SpliceAI max delta = 0.00, indicating no predicted splice impact. Per VCEP instructions, the SpliceAI score alone can be applied if VarSeak is unable to accept the variant type. The variant is a coding missense with no predicted effect on splicing.
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: 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
107 / 1,583,178 alleles
gnomAD v4.1: 107 / 1,583,178 alleles. Recorded AF 6.75856e-05. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.52477e-05; MAF= 0.00852%, 19/222880 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000749866; MAF= 0.07499%, 14/18670 alleles, homozygotes = 0); grpmax FAF= 0.00037662.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016284876777765715, 3/18422 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
12 reported laboratory submissions
6 Uncertain significance · 4 Likely benign · 2 Benign.
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV56549582, n = 1 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: 4 met · 16 not met · 0 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.154G>A (p.Glu52Lys) has a GroupMax filtering allele frequency of 0.08611% (0.0008611) in gnomAD v4.1, which exceeds the VHL VCEP BA1 stand-alone benign threshold of 0.0156% (0.000156).
The variant is observed in 107 of 1,583,178 alleles in gnomAD v4.1, including 1 homozygote, with highest frequency in the African/African American population (78/74,388 alleles, 0.1049%).
BA1 as stand-alone benign is independently sufficient to classify the variant as Benign regardless of other evidence criteria.
BS1 is also met at strong benign level: gnomAD v4 GroupMax FAF 0.0008611 exceeds the VCEP BS1 threshold of 0.0000156.
BP4 is met at supporting benign level: SpliceAI predicts no splicing impact (max delta = 0.00).
The variant was observed in 1-2 VHL families (Olschwang 1998, Gallou 2004) but this does not meet PS4 thresholds and is outweighed by population frequency data.
ClinVar expert panel (ClinGen VHL VCEP) classifies this variant as Benign (VCV000161402).
REVEL score of 0.559 does not meet the VHL VCEP PP3 threshold of ≥0.664. BayesDel score of -0.059 is consistent with a benign prediction.
The variant alters codon 52, which is upstream of the second VHL initiation codon (Met54); only pVHL30 is affected while pVHL19 remains intact. This N-terminal region is outside recognized VHL critical functional domains.
No criteria match.
Met · 4
BA1 Stand aloneVHL VCEP BA1 threshold: GroupMax FAF ≥ 0.000156 (0.0156%) in gnomAD v4. This variant has gnomAD v4 GroupMax FAF = 0.0008611 (0.08611%) in the African/African American population (78/74,388 alleles, 1 homozygote). This is approximately 5.5-fold above the BA1 cutoff. The variant is also observed in gnomAD v2.1 with grpmax FAF 0.00037662 in the same population group. BA1 is met as stand-alone benign evidence, independently sufficient to classify this variant as benign regardless of other criteria. Details ▾Hide ▴
Evidence considered
- gnomAD v4 GrpMax FAF 0.0008611 (0.08611%) ≥ BA1 cutoff 0.000156 (0.0156%).
- gnomAD v2.1 GrpMax FAF 0.00037662.
- Highest in African/African American: 78/74
- 388 alleles
- AF 0.1049%
- 1 homozygote.
Sources
BS1 StrongVHL VCEP BS1 threshold: GroupMax FAF ≥ 0.0000156 (0.00156%) in gnomAD v4. This variant has gnomAD v4 GroupMax FAF = 0.0008611 (0.08611%), which is approximately 55-fold above the BS1 cutoff. BS1 is met as strong benign evidence. Note: BA1 (stand-alone) subsumes BS1; both are independently met. Details ▾Hide ▴
Evidence considered
- gnomAD v4 GrpMax FAF 0.0008611 (0.08611%) ≥ BS1 cutoff 0.0000156 (0.00156%).
Sources
BP4 SupportingVHL VCEP BP4: missense predictors should not be used for BP4, but BP4 can be applied to assess lack of splicing impact with SpliceAI ≤ 0.1 and VarSeak Class 1 or 2. This variant has SpliceAI max delta = 0.00, indicating no predicted splice impact. Per VCEP instructions, the SpliceAI score alone can be applied if VarSeak is unable to accept the variant type. The variant is a coding missense with no predicted effect on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 (no predicted splicing impact).
Still missing
- VarSeak data not available
- but SpliceAI alone is acceptable per VCEP instructions.
Sources
Not met · 16 · evaluated, threshold not reached
PS1 PS1 requires a different nucleotide change at the same codon previously classified as pathogenic by the VHL VCEP. No VCEP-interpreted pathogenic variant at codon 52 with a different nucleotide change was identified. E52K itself is the variant under assessment; no comparator missense at codon 52 (e.g., E52Q, E52X) has been established as pathogenic under VCEP specifications. Details ▾Hide ▴
Evidence considered
- No VCEP-classified pathogenic comparator at codon 52.
PS2 No de novo occurrence with confirmed maternity and paternity was identified for this variant in the reviewed literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No de novo testing data available.
PS3 No validated in vitro or in vivo functional assay demonstrating a damaging effect of E52K on VHL protein function (HIF1/2a degradation, VBC complex stability, or ECM/fibronectin binding). Computational modeling in PMID:26211615 suggests E52K may alter pVHL-N conformation, but this is in silico prediction and does not meet the Brnich et al. framework for PS3 functional evidence. Details ▾Hide ▴
Evidence considered
- No variant-specific functional assay data available
- in silico modeling (PMID:26211615) does not meet PS3 threshold.
Still missing
- No functional assay data for E52K.
PS4 The variant has been reported in a small number of VHL probands: one type 1 VHL patient in Olschwang et al. (1998, family V285) and one family (285a) in Gallou et al. (2004) with renal involvement. This level of proband evidence (approximately 1-2 probands) falls far below even the PS4_Supporting threshold of 1 point under the VHL VCEP proband scoring tables. Additionally, the variant is present in gnomAD at appreciable frequency, further weakening any case-control argument. Details ▾Hide ▴
Evidence considered
- 1-2 reported VHL probands
- insufficient for PS4 scoring.
- gnomAD v4: 107 alleles
- AF 6.76e-5
- 1 homozygote.
Still missing
- Larger proband counts would be needed to reach PS4 thresholds.
Sources
PM1 Codon 52 resides in the pVHL N-terminal acidic repeat region (AA 1-53), upstream of the second initiation codon (Met54). This region is not a recognized VHL germline hotspot or critical functional domain (Beta domain: AA 63-154, Alpha domain: AA 155-192, Second Beta: AA 193-204). COSMIC reports only 1 somatic instance at this residue, well below the 10-instance threshold for PM1_Moderate. Details ▾Hide ▴
Evidence considered
- Codon 52 outside VHL critical domains.
- 1 COSMIC entry at this residue
- below PM1 threshold.
- Not a statistically significant hotspot (cancerhotspots.org).
Sources
PM2 VHL VCEP PM2_Supporting requires GroupMax FAF ≤ 0.00000156 (0.000156%) in gnomAD v4. This variant has gnomAD v4 GroupMax FAF = 0.0008611 (0.08611%), which is approximately 552-fold above the PM2 threshold. The variant is also present in gnomAD v2.1 (19 alleles, grpmax FAF 0.00037662). Details ▾Hide ▴
Evidence considered
- gnomAD v4: 107/1
- 583
- 178 alleles
- GrpMax FAF 0.0008611.
- gnomAD v2.1: 19/222
- 880 alleles
- GrpMax FAF 0.00037662.
Sources
PM5 PM5 requires a different missense change at the same residue previously classified as pathogenic by the VHL VCEP. No alternative missense variant at codon 52 (e.g., E52Q, E52D, E52X) has been reported and classified as pathogenic under VCEP specifications. The pm5_candidates search found no eligible comparator variants. Details ▾Hide ▴
Evidence considered
- No VCEP-classified pathogenic comparator missense at codon 52.
- pm5_candidates search returned zero eligible candidates.
PM6 No assumed de novo occurrence without maternity/paternity confirmation was identified for this variant in the reviewed literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No de novo reports identified.
Still missing
- No de novo testing data available.
PP1 No co-segregation data meeting VHL VCEP thresholds was identified. The Olschwang et al. (1998) report includes 1 affected/1 unaffected family member tested, which provides no meiosis count toward PP1 thresholds (minimum 3-4 meioses for supporting). Details ▾Hide ▴
Evidence considered
- Olschwang 1998: 1 affected/0 unaffected carriers tested in family V285
- no segregation meioses.
Still missing
- No multi-generational segregation data available.
Sources
PP3 VHL VCEP PP3 for missense variants requires REVEL score ≥ 0.664. This variant has REVEL = 0.559, which falls below the threshold. BayesDel score = -0.059 (benign-leaning). SpliceAI max delta = 0.00 (no predicted splicing impact), so PP3 for splicing is also not applicable. Details ▾Hide ▴
Evidence considered
- REVEL 0.559 < 0.664 VCEP threshold.
- BayesDel -0.059 (benign-weighted).
- SpliceAI 0.00 (no splicing impact).
Sources
BS2 VHL VCEP BS2 requires at least 3 individuals ≥65 years old, unaffected, harboring this variant. While gnomAD v4 reports 1 homozygote and 107 total alleles, no clinical phenotype data on unaffected status of these population individuals is available. The criteria-specific clinical data for BS2 (age, full phenotyping, VHL cancer screening) are not available from population databases alone. Details ▾Hide ▴
Evidence considered
- gnomAD v4: 107 alleles
- 1 homozygote in population cohort.
- No clinical phenotyping data available for BS2 criteria.
Still missing
- Lack of clinical phenotype and age data on gnomAD individuals.
Sources
BS3 No validated functional assay demonstrating benign effect (WT-like function) of E52K on HIF1/2a degradation, VBC complex stability, or ECM/fibronectin binding. The variant is located upstream of the Met54 second initiation codon and does not affect pVHL19, which retains full tumor suppressor function; however, no direct experimental evidence confirming benign functional effect of E52K was identified. Details ▾Hide ▴
Evidence considered
- No variant-specific functional assay demonstrating benign effect available.
- Theoretical: E52K alters only pVHL30
- leaving pVHL19 intact
- but this is not experimental BS3 evidence.
Still missing
- No functional assay data for E52K.
BS4 No lack-of-segregation data available. The Olschwang et al. (1998) family V285 has 1 affected/0 unaffected carriers, providing no segregation information for BS4. No multi-family segregation data was identified. Details ▾Hide ▴
Evidence considered
- No segregation data meeting BS4 criteria.
Still missing
- No segregation data available.
BP2 BP2_Strong would apply if the variant were observed in the homozygous state in an individual without VHL disease or congenital polycythemia. gnomAD v4 reports 1 homozygous individual, but no clinical phenotype data are available to confirm absence of VHL-related disease or congenital polycythemia. Without confirmatory clinical data, BP2 cannot be applied. Details ▾Hide ▴
Evidence considered
- gnomAD v4: 1 homozygote reported
- but no clinical phenotype data.
Still missing
- Clinical phenotype of gnomAD v4 homozygous individual unknown.
- No phase-confirmed trans observations.
Sources
BP5 BP5 requires two or more co-occurrences with pathogenic variants in a different gene that fully explain the patient's phenotype, with specific phenotype non-overlap criteria. No such co-occurrence evidence was identified for this variant. Details ▾Hide ▴
Evidence considered
- No co-occurrence data with pathogenic variants in other genes.
Still missing
- No co-occurrence data available.
PS5 No reputable source reports this variant as pathogenic. ClinVar classifies it as Benign by the ClinGen VHL Variant Curation Expert Panel (expert panel review). The majority of clinical laboratory submissions are Uncertain Significance (6) or Likely benign/Benign (6). Details ▾Hide ▴
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical splice). NM_000551.3:c.154G>A is a missense variant (p.Glu52Lys) and does not fall into any PVS1 null-variant bucket. Additionally, the variant is upstream of the second initiation codon (Met54) and alters only pVHL30, not pVHL19. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 52
- not a null variant.
PP2 VCEPVHL VCEP explicitly states PP2 is not applicable. gnomAD shows VHL is not intolerant to missense variation (Z score = -0.39); benign missense variants exist in VHL. Details ▾Hide ▴
PP4 VCEPVHL VCEP states PP4 is not applicable; combined with PS4 to avoid double counting probands. Details ▾Hide ▴
PP5 VCEPVHL VCEP states PP5 is not applicable. Criterion not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Details ▾Hide ▴
BP1 VCEPVHL VCEP states BP1 is not applicable. Truncating variants account for only a portion of disease-causing variants in VHL; missense variants are a well-established mechanism of disease. Details ▾Hide ▴
BP3 N/APre-skipped: substitution variant, BP3 applies to in-frame indels in repetitive regions. Details ▾Hide ▴
Evidence considered
- Not applicable (substitution variant).
BP7 N/ABP7 applies only to silent (synonymous) or intronic variants with no predicted splice impact and PhyloP ≤ 0.2. This variant is a missense substitution (p.Glu52Lys), not a silent or intronic variant. Details ▾Hide ▴
Identifiers
- Gene
- VHL
- Transcript
- NM_000551.3
- Coding (HGVS c.)
- NM_000551.3:c.154G>A
- Protein (HGVS p.)
- NP_000542.1:p.(Glu52Lys)
- GRCh38
- chr3:10142001 G>A
- GRCh37
- chr3:10183685 G>A
- ClinVar
- 161402
- COSMIC
- COSV56549582
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
107 / 1,583,178 alleles
AF 6.76e-05 · 1 homozygotes · FAF 0.000861
gnomAD v2.1
19 / 222,880 alleles
AF 8.52e-05 · 0 homozygotes · FAF 0.000377
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.8e-05 · 107 / 1,583,178 alleles · 1 hom · FAF 0.00086
| African/African American78 / 74,388 | 0.0011 hom |
| Middle Eastern5 / 5,852 | 0.00085 |
| Remaining individuals11 / 61,296 | 0.00018 |
| Admixed American4 / 55,306 | 7.2e-05 |
| East Asian2 / 43,106 | 4.6e-05 |
| South Asian3 / 87,394 | 3.4e-05 |
| European (non-Finnish)4 / 1,166,190 | 3.4e-06 |
0 alternate alleles recorded in 3 other groups: European (Finnish), Amish, Ashkenazi Jewish.
gnomAD v2.1
AF 8.5e-05 · 19 / 222,880 alleles · 0 hom · FAF 0.00038
| African/African American14 / 18,670 | 0.00075 |
| Remaining individuals1 / 6,032 | 0.00017 |
| Admixed American2 / 29,928 | 6.7e-05 |
| East Asian1 / 15,778 | 6.3e-05 |
| South Asian1 / 26,200 | 3.8e-05 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, European (Finnish), European (non-Finnish).
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.75856e-05; MAF= 0.00676%, 107/1583178 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00104856; MAF= 0.10486%, 78/74388 alleles, homozygotes = 1); grpmax FAF= 0.0008611.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.52477e-05; MAF= 0.00852%, 19/222880 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000749866; MAF= 0.07499%, 14/18670 alleles, homozygotes = 0); grpmax FAF= 0.00037662.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016284876777765715, 3/18422 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.559
- BayesDel
- -0.059
How the predictions were used
BP4 SupportingVHL VCEP BP4: missense predictors should not be used for BP4, but BP4 can be applied to assess lack of splicing impact with SpliceAI ≤ 0.1 and VarSeak Class 1 or 2. This variant has SpliceAI max delta = 0.00, indicating no predicted splice impact. Per VCEP instructions, the SpliceAI score alone can be applied if VarSeak is unable to accept the variant type. The variant is a coding missense with no predicted effect on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.00 (no predicted splicing impact).
Still missing
- VarSeak data not available
- but SpliceAI alone is acceptable per VCEP instructions.
Sources
PP3 VHL VCEP PP3 for missense variants requires REVEL score ≥ 0.664. This variant has REVEL = 0.559, which falls below the threshold. BayesDel score = -0.059 (benign-leaning). SpliceAI max delta = 0.00 (no predicted splicing impact), so PP3 for splicing is also not applicable. Details ▾Hide ▴
Evidence considered
- REVEL 0.559 < 0.664 VCEP threshold.
- BayesDel -0.059 (benign-weighted).
- SpliceAI 0.00 (no splicing impact).
Sources
BP7 N/ABP7 applies only to silent (synonymous) or intronic variants with no predicted splice impact and PhyloP ≤ 0.2. This variant is a missense substitution (p.Glu52Lys), not a silent or intronic variant. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.559. BayesDel score = -0.0592421.
10 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
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PMID 11257211 ↗Is the P25L a "real" VHL mutation?Rothberg PG et al. · 2001E52K was reported in one tested individual with type 1 VHL disease (no pheochromocytoma), citing Olschwang et al. 1998. The study's primary focus was on P25L as a rare VHL variant; both P25L and P86R were found in a VHL proband but E52K is discussed in the context of other mutations upstream of the second initiation codon.Names this variant
Quoted passage
E46X and E52K were associated with type 1 (no pheochromocytoma) VHL in one tested individual for E52K, but the number of affected individuals with E46X was not reported
Introduction paragraph 4; Discussion paragraph 6
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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 2015 standards and guidelines for sequence variant interpretation. Provides the generic framework for variant classification but does not discuss any specific VHL variants including E52K.Does not name this variant
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PMID 26211615 ↗Isoform-specific interactions of the von Hippel-Lindau tumor suppressor protein.Minervini G et al. · 2015E52K was analyzed by ab initio structural modeling of the pVHL30 N-terminal tail. The mutation inserts a positive charge (lysine) into a negatively charged triplet formed by glutamic acid residues 51-53. Computational modeling suggests this may reduce conformational flexibility and promote a malignant phenotype through altered protein-protein interactions. Variant was cited as found in VHL disease type I (sourced from UniProt database).Names this variant
Quoted passage
Finally the E52K mutation inserts a positive charge in a negative triplet formed by the glutamic acid residues 51–53. Considering the mainly acidic pVHL-N composition, this mutation should promote an irregular salt-bridge bond, reducing conformational flexibility and stabilizing an unfolded knot promoting a malignant phenotype.
Results and Discussion, paragraphs 1-2; Figure 1A; Figure 2
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PMID 9829912 ↗Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma.Olschwang S et al. · 1998E52K (c.154G>A, G154A) was identified in a type 1 VHL patient (family V285). The variant was reported among 61 DNA variants detected in 92 unrelated VHL patients screened by DGGE and direct sequencing. One affected and no unaffected family members were tested.Names this variant
Quoted passage
V285 | 1 | 1 | G154A | E52K | 1/0 | 1/0
Table 3 (Germline DNA Variations of Unknown Biological Significance)
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PMID 10612827 ↗UMD (Universal mutation database): a generic software to build and analyze locus-specific databases.Béroud C et al. · 2000Describes the UMD (Universal Mutation Database) software platform for building locus-specific mutation databases. The VHL gene is listed as one of nine genes for which an LSDB was developed, but no specific VHL variants including E52K are discussed.Does not name this variant
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PMID 12202531 ↗Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study.Dollfus H et al. · 2002No paper-specific finding is recorded.
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PMID 15300849 ↗Genotype-phenotype correlation in von Hippel-Lindau families with renal lesions.Gallou C et al. · 2004Family 285a harbored the E52K (c.154G>A) missense mutation. The family was among three pedigrees with mutations upstream of the second methionine initiation site (Met54), all of which belonged to the group with kidney cancer, exhibiting mild to severe renal phenotype. This family was classified in the renal involvement group for genotype-phenotype correlation analysis.Names this variant
Quoted passage
three families with mutation upstream the second methionine initiation site belonged to the group with kidney cancer, exhibiting mild to severe renal phenotype
Table 2 (Molecular Details in 126 VHL Families); Results, paragraph on genotype-phenotype correlation
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PMID 20301636 ↗Von Hippel-Lindau Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 24055113 ↗Actionable, pathogenic incidental findings in 1,000 participants' exomes.Dorschner MO et al. · 2013No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
107 / 1,583,178 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
6 Uncertain significance · 4 Likely benign · 2 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/161402/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-10183685-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-10142001-G-A?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-10142001-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000551.3%3Ac.154G…
- OncoKB ↗www.oncokb.org/gene/VHL/E52K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=121591678
- 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= 6.75856e-05; MAF= 0.00676%, 107/1583178 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00104856; MAF= 0.10486%, 78/74388 alleles, homozygotes = 1); grpmax FAF= 0.0008611.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 8.52477e-05; MAF= 0.00852%, 19/222880 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000749866; MAF= 0.07499%, 14/18670 alleles, homozygotes = 0); grpmax FAF= 0.00037662.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016284876777765715, 3/18422 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (4 clinical laboratories) and as Benign (2 clinical laboratories) and as Benign by ClinGen VHL Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 161402)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.559. BayesDel score = -0.0592421.
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; COSV56549582, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.