About VHL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
VHL c.104C>T, p.(Ala35Val)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS1Strong
BS1 · strong
Per VHL VCEP v1.1.0, BS1 is met at Strong strength. The gnomAD v4.1 GroupMax Filtering Allele Frequency is 0.0001103 (0.01103%), which exceeds the VCEP BS1 cutoff of ≥0.0000156 (0.00156%). The variant is present at 16 alleles in gnomAD v4.1 (AF = 1.04e-5) with the highest subpopulation frequency in the South Asian population (AF = 0.000179, 15/83,692 alleles). This frequency is higher than expected for von Hippel-Lindau disease.
BP4Supporting
BP4 · supporting
Per VHL VCEP v1.1.0, BP4 can be applied to assess lack of splicing impact. SpliceAI predicts no splicing effect (max delta score = 0.00, ≤0.1). Per VCEP guidance, SpliceAI alone may be applied when VarSeak is unable to accept the variant type. Missense predictors are explicitly excluded from BP4 per VCEP, but splicing assessment via SpliceAI is permitted. No splice effect is predicted.
Recorded classification: Likely 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 Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BS1 strong, BP4 supporting; maps to Likely 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
16 / 1,544,318 alleles
gnomAD v4.1: 16 / 1,544,318 alleles. Recorded AF 1.03606e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.78444e-06; MAF= 0.00068%, 1/147396 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 4.47307e-05; MAF= 0.00447%, 1/22356 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
3 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Context only
ClinVar ↗
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
29 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 9 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.104C>T (p.Ala35Val) is a missense variant in exon 1 of VHL, located in the N-terminal region prior to the p19 Met54 initiation site and outside all critical functional domains (Beta: AA63-154, Alpha: AA156-192, Second Beta: AA193-204).
This variant is present in gnomAD v4.1 at 16 of 1,544,318 alleles (allele frequency 1.04e-5) with a GroupMax Filtering Allele Frequency of 0.01103% (0.0001103) in the South Asian population, exceeding the VHL VCEP BS1 threshold of ≥0.00156% (BS1_Strong).
SpliceAI predicts no splicing impact (max delta score = 0.00), meeting the VHL VCEP BP4 criterion for lack of splice effect at Supporting strength.
REVEL score is 0.307, below the VHL VCEP PP3 threshold of ≥0.664. BayesDel score is -0.264 (benign direction). In silico predictors do not support pathogenicity.
No variant-specific functional data, segregation data, de novo observations, or proband phenotype data are available. The variant has not been reported in COSMIC and does not lie in a statistically significant mutational hotspot.
ClinVar classifies this variant as Uncertain significance (variation ID 526678) based on 3 clinical laboratory submissions with no expert panel review.
Applying the VHL VCEP v1.1.0 classification rules: BS1_Strong (1 strong benign) + BP4_Supporting (1 supporting benign) meets Rule 18 criteria for Likely Benign.
No criteria match.
Met · 2
BS1 StrongPer VHL VCEP v1.1.0, BS1 is met at Strong strength. The gnomAD v4.1 GroupMax Filtering Allele Frequency is 0.0001103 (0.01103%), which exceeds the VCEP BS1 cutoff of ≥0.0000156 (0.00156%). The variant is present at 16 alleles in gnomAD v4.1 (AF = 1.04e-5) with the highest subpopulation frequency in the South Asian population (AF = 0.000179, 15/83,692 alleles). This frequency is higher than expected for von Hippel-Lindau disease. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 16/1
- 544
- 318 alleles (AF=1.04e-5)
- grpmax FAF=0.0001103 (0.01103%). VCEP BS1 cutoff: ≥0.00156%. 0.01103% > 0.00156%. gnomAD v2.1: 1/147
- 396 alleles (AF=6.78e-6). South Asian enrichment: 15/83
- 692 alleles (AF=0.0179%).
Sources
BP4 SupportingPer VHL VCEP v1.1.0, BP4 can be applied to assess lack of splicing impact. SpliceAI predicts no splicing effect (max delta score = 0.00, ≤0.1). Per VCEP guidance, SpliceAI alone may be applied when VarSeak is unable to accept the variant type. Missense predictors are explicitly excluded from BP4 per VCEP, but splicing assessment via SpliceAI is permitted. No splice effect is predicted. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00. VCEP BP4 rule: 'BP4 can be applied to assess lack of splicing impact
- with concordance of Splice AI (≤0.1).' VarSeak not assessed (splice predictor only
- VCEP allows SpliceAI alone).
Still missing
- VarSeak splice prediction not available for this variant type. VCEP allows SpliceAI alone.
Sources
Not met · 18 · evaluated, threshold not reached
PS1 PS1 requires a different nucleotide change producing the same amino acid change (p.Ala35Val) previously classified as pathogenic by the VHL VCEP. The only alternative nucleotide change that could produce A35V at codon 35 is c.104C>A; this variant has not been observed or classified as pathogenic by VHL VCEP. No qualifying comparator exists. Details ▾Hide ▴
Evidence considered
- Residue position 35: reference Alanine (GCN codons). c.104C>T produces A35V. The only alternate path to A35V is c.104C>A
- which has no pathogenic classification by VCEP. No VCEP-classified comparator at this residue.
PS2 No de novo observations reported for NM_000551.3:c.104C>T. PS2 requires confirmed de novo occurrence with maternity and paternity confirmed. No proband data meeting VCEP PS2 phenotype scoring criteria were identified in the evidence packet or literature. Details ▾Hide ▴
Evidence considered
- No de novo observations in ClinVar submissions
- literature abstracts
- or full-text papers reviewed.
Still missing
- No proband or trio sequencing data available.
PS3 No variant-specific functional data available for p.Ala35Val. The VHL VCEP recognizes HIF1/2a degradation assays, VBC complex stability assays, and fibronectin/ECM assays as acceptable functional evidence. None of these have been performed for this variant. The VCEP Functional Assay SVI documentation spreadsheet does not list A35V. Details ▾Hide ▴
Evidence considered
- VCEP-approved functional assays (HIF1/2a degradation
- VBC complex stability
- fibronectin binding/ECM) have not been performed for p.Ala35Val. VHL_Functional_Assay_SVI_documentation.xlsx does not include codon 35 variants.
Still missing
- No functional studies conducted for this specific variant.
PS4 No proband count data meeting VCEP PS4 phenotype scoring criteria. ClinVar reports this variant as Uncertain significance from 3 clinical laboratories, with no expert panel submissions. No case-level publications with proband phenotypes were identified. VCEP PS4 requires proband scoring using specific Danish Criteria and phenotype point tables; no qualifying probands were found. Details ▾Hide ▴
Evidence considered
- ClinVar variation ID 526678: VUS
- 3 clinical laboratory submissions
- no expert panel review. No proband phenotype data available.
Still missing
- No proband phenotypes matching VCEP PS4 criteria.
Sources
PM1 Codon 35 is located in the N-terminal region of VHL (residues 1-54), upstream of both the p19 initiation site (Met54) and the critical functional domains. The critical domains per VHL VCEP are: Beta domain (AA 63-154), Alpha domain (AA 156-192), and Second Beta domain (AA 193-204). Codon 35 is outside all critical domains. CancerHotspots.org does not identify this residue as a significant hotspot (exact variant not listed, residue not significant). COSMIC reports no somatic occurrences. Details ▾Hide ▴
Evidence considered
- Position 35 is in the N-terminal region (AA 1-54)
- outside critical Beta (63-154)
- Alpha (156-192)
- and Second Beta (193-204) domains. No germline hotspot. No somatic incidence in COSMIC. CancerHotspots: residue not significant.
PM2 Per VHL VCEP v1.1.0, PM2_Supporting requires absence from gnomAD or GroupMax Filtering Allele Frequency (FAF) ≤ 0.00000156 (0.000156%) in gnomAD v4. The observed gnomAD v4.1 grpmax FAF is 0.0001103 (0.01103%), which exceeds the PM2_Supporting threshold by approximately 70-fold. This variant is present at 16 alleles in gnomAD v4.1 (AF = 1.04e-5) and 1 allele in gnomAD v2.1. PM2 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 16/1
- 544
- 318 alleles (AF=1.04e-5)
- grpmax FAF=0.0001103 (0.01103%). VCEP PM2_Supporting cutoff: ≤0.000156%. 0.01103% >> 0.000156%. gnomAD v2.1: 1/147
- 396 alleles. Absent from gnomAD-Canada.
Sources
PM5 PM5 requires a different pathogenic missense variant at the same residue (Ala35) classified by the VHL VCEP. No alternative pathogenic missense variants at codon 35 were identified in ClinVar or the evidence packet. The pm5_candidates analysis found zero same-residue candidates. The only alternative amino acid change at codon 35 (via c.104C>A) has no pathogenic classification. Details ▾Hide ▴
Evidence considered
- No pathogenic VCEP-classified missense variant at codon 35 identified. pm5_candidates analysis: 0 same-residue candidates found.
Still missing
- No comparator variant at codon 35.
PM6 PM6 requires assumed de novo occurrence without confirmation of maternity and paternity. No de novo observations — confirmed or assumed — have been reported for this variant in any available source. Details ▾Hide ▴
Evidence considered
- No de novo observations in ClinVar or literature.
Still missing
- No de novo data available.
PP1 PP1 requires co-segregation data with disease in multiple affected family members. No segregation data (meioses counts) are available for NM_000551.3:c.104C>T. VHL VCEP requires 3-4 meioses for Supporting, 5-6 for Moderate, and >7 across ≥2 families for Strong. Details ▾Hide ▴
Evidence considered
- No segregation or family studies identified for this variant.
Still missing
- No family segregation data.
PP3 Per VHL VCEP v1.1.0, PP3 for missense variants requires REVEL score ≥ 0.664. The observed REVEL score for p.Ala35V is 0.307, well below the threshold. BayesDel score is -0.264 (benign direction). SpliceAI max delta is 0.00 (no predicted splice impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.307 (VCEP cutoff ≥0.664). BayesDel: -0.264 (benign). SpliceAI max delta: 0.00. All in silico predictors are below VCEP pathogenic thresholds.
Sources
BA1 Per VHL VCEP v1.1.0, BA1 requires GroupMax Filtering Allele Frequency ≥ 0.000156 (0.0156%) in gnomAD v4. The observed grpmax FAF is 0.0001103 (0.01103%), which is below the BA1 threshold. BA1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF: 0.0001103 (0.01103%). VCEP BA1 cutoff: ≥0.0156%. 0.01103% < 0.0156%
- BA1 threshold not reached.
Sources
BS2 VHL VCEP BS2 requires at least 3 individuals ≥65 years old harboring the variant, unaffected by VHL-related cancers. No such data are available in the evidence packet. The gnomAD population data do not include age or phenotype information. Details ▾Hide ▴
Evidence considered
- No data on healthy individuals ≥65 years old harboring this variant.
Still missing
- No phenotype or age data for gnomAD carriers.
BS3 VHL VCEP BS3 requires well-established functional studies showing no damaging effect (HIF1/2a degradation preserved, VBC complex stability unaffected, ECM/fibronectin binding unaffected). No functional studies — benign or pathogenic — have been performed for p.Ala35Val. The VCEP Functional Assay SVI documentation does not include this variant. Details ▾Hide ▴
Evidence considered
- No variant-specific benign functional data available. VHL_Functional_Assay_SVI_documentation.xlsx has no entries for codon 35.
Still missing
- No functional studies for this variant.
BS4 VHL VCEP BS4 requires lack of segregation in affected family members who fulfill Danish Criteria for VHL. No segregation data — positive or negative — are available for NM_000551.3:c.104C>T. Details ▾Hide ▴
Evidence considered
- No segregation or family data available for this variant.
Still missing
- No family segregation data.
BP2 VHL VCEP BP2 requires observation in trans with a pathogenic VHL variant (phase confirmed, no congenital polycythemia), or in homozygous state without disease, or in cis with three or more pathogenic VHL variants. No such observations are available for this variant. Details ▾Hide ▴
Evidence considered
- No evidence of trans
- cis
- or homozygous observations with pathogenic VHL variants.
Still missing
- No phase data or co-occurrence data with other VHL variants.
BP5 VHL VCEP BP5 requires two or more co-occurrences with pathogenic variants in a different gene that fully explain the patient's phenotype. No such co-occurrence data are available for this variant. Details ▾Hide ▴
Evidence considered
- No evidence of co-occurrence with pathogenic variants in other genes explaining phenotype.
Still missing
- No co-occurrence data.
BP7 VHL VCEP BP7 is restricted to synonymous (silent) or intronic variants where BP4 is met for lack of splice effect and the PhyloP score is ≤0.2. NM_000551.3:c.104C>T is a missense variant (p.Ala35Val), not a silent or intronic variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- VHL VCEP BP7 rule: 'If BP4 is met for lack of splice effect
- BP7 can be applied to silent or intronic variants where the PhyloP score is ≤0.2.' This variant is missense
- not silent/intronic. BP7 not applicable.
Sources
PS5 PS5 is not explicitly defined in the VHL VCEP v1.1.0 criteria set. Under generic ACMG/AMP, PS5 requires a reputable source to report the variant as pathogenic. ClinVar classifies this variant as Uncertain significance (3 clinical laboratories, criteria provided single submitter). No reputable source reports this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance (variation ID 526678). No pathogenic classification from any submitter.
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical splice, initiation codon, exon deletion). NM_000551.3:c.104C>T is a missense variant (p.Ala35Val). Per VHL VCEP v1.1.0, PVS1 is restricted to truncating variants after codon 54; this variant is a substitution at codon 35 in exon 1. Details ▾Hide ▴
Evidence considered
- Missense substitution at c.104C>T
- resulting in p.Ala35Val. Not a null variant. Codon 35 is prior to codon 54 (the p19 Met54 initiation site). VCEP PVS1 rule: 'Do not apply PVS1 for truncations that occur prior to Codon 54.'
PM3 VCEPVHL is an autosomal dominant disorder. PM3 applies to recessive disorders where the variant is detected in trans with a pathogenic variant. Per VHL VCEP, PM3 applicability = 'Not applicable.' Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame insertions/deletions and stop-loss variants. NM_000551.3:c.104C>T is a missense substitution, not a protein-length-altering variant. Details ▾Hide ▴
No further detail was recorded.
PP2 VCEPPer VHL VCEP v1.1.0, PP2 is not applicable. VHL is not intolerant to missense variation (gnomAD missense Z-score = -0.39), and there is evidence of benign/common missense variants in VHL. The VCEP explicitly instructs: 'Do not use.' Details ▾Hide ▴
Evidence considered
- VHL VCEP: PP2 applicability = 'Not applicable'. VHL gnomAD missense Z-score = -0.39. Benign missense variation documented in VHL.
Sources
PP4 VCEPPer VHL VCEP v1.1.0, PP4 is not applicable as an independent criterion. The VCEP instructs to combine PP4 with PS4 to avoid double-counting probands. No proband phenotype data are available to contribute to PS4 scoring. Details ▾Hide ▴
Evidence considered
- VHL VCEP: PP4 applicability = 'Not applicable'. Instructions: 'Combine with PS4 to avoid double counting probands.'
Sources
PP5 VCEPPer VHL VCEP v1.1.0, PP5 is not applicable. The ClinGen Sequence Variant Interpretation VCEP Review Committee recommends this criterion not be used. ClinVar classification is Uncertain significance, not pathogenic. Details ▾Hide ▴
BP1 VCEPPer VHL VCEP v1.1.0, BP1 is not applicable. The VCEP states: 'This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants.' Details ▾Hide ▴
Evidence considered
- VHL VCEP: BP1 applicability = 'Not applicable'. Truncating variants account for only a portion of VHL disease-causing variants.
Sources
BP3 N/ASkipped per workflow instruction. Note: codon 35 falls within the 8x GXEEX repeat motif (AA14-AA48) in the 5' end of VHL p30, which is the only region where VHL VCEP permits BP3 application for in-frame deletions/insertions in repetitive regions. BP3 could theoretically be considered for in-frame indels in this region, but the user flagged BP3 as trivially not_applicable (substitution variant). Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPPer VHL VCEP v1.1.0, BP6 is not applicable. The ClinGen Sequence Variant Interpretation VCEP Review Committee recommends this criterion not be used. Details ▾Hide ▴
Identifiers
- Gene
- VHL
- Transcript
- NM_000551.3
- Coding (HGVS c.)
- NM_000551.3:c.104C>T
- Protein (HGVS p.)
- NP_000542.1:p.(Ala35Val)
- GRCh38
- chr3:10141951 C>T
- GRCh37
- chr3:10183635 C>T
- ClinVar
- 526678
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
16 / 1,544,318 alleles
AF 1.04e-05 · 0 homozygotes · FAF 0.00011
gnomAD v2.1
1 / 147,396 alleles
AF 6.78e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1e-05 · 16 / 1,544,318 alleles · 0 hom · FAF 0.00011
| South Asian15 / 83,692 | 0.00018 |
| Remaining individuals1 / 59,696 | 1.7e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish).
gnomAD v2.1
AF 6.8e-06 · 1 / 147,396 alleles · 0 hom
| South Asian1 / 22,356 | 4.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.03606e-05; MAF= 0.00104%, 16/1544318 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000179229; MAF= 0.01792%, 15/83692 alleles, homozygotes = 0); grpmax FAF= 0.0001103.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.78444e-06; MAF= 0.00068%, 1/147396 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 4.47307e-05; MAF= 0.00447%, 1/22356 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.307
- BayesDel
- -0.264
How the predictions were used
BP4 SupportingPer VHL VCEP v1.1.0, BP4 can be applied to assess lack of splicing impact. SpliceAI predicts no splicing effect (max delta score = 0.00, ≤0.1). Per VCEP guidance, SpliceAI alone may be applied when VarSeak is unable to accept the variant type. Missense predictors are explicitly excluded from BP4 per VCEP, but splicing assessment via SpliceAI is permitted. No splice effect is predicted. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00. VCEP BP4 rule: 'BP4 can be applied to assess lack of splicing impact
- with concordance of Splice AI (≤0.1).' VarSeak not assessed (splice predictor only
- VCEP allows SpliceAI alone).
Still missing
- VarSeak splice prediction not available for this variant type. VCEP allows SpliceAI alone.
Sources
PP3 Per VHL VCEP v1.1.0, PP3 for missense variants requires REVEL score ≥ 0.664. The observed REVEL score for p.Ala35V is 0.307, well below the threshold. BayesDel score is -0.264 (benign direction). SpliceAI max delta is 0.00 (no predicted splice impact). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.307 (VCEP cutoff ≥0.664). BayesDel: -0.264 (benign). SpliceAI max delta: 0.00. All in silico predictors are below VCEP pathogenic thresholds.
Sources
BP7 VHL VCEP BP7 is restricted to synonymous (silent) or intronic variants where BP4 is met for lack of splice effect and the PhyloP score is ≤0.2. NM_000551.3:c.104C>T is a missense variant (p.Ala35Val), not a silent or intronic variant. BP7 does not apply. Details ▾Hide ▴
Evidence considered
- VHL VCEP BP7 rule: 'If BP4 is met for lack of splice effect
- BP7 can be applied to silent or intronic variants where the PhyloP score is ≤0.2.' This variant is missense
- not silent/intronic. BP7 not applicable.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.307. BayesDel score = -0.264275.
6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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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.This is the ACMG/AMP standards and guidelines for sequence variant interpretation. NM_000551.3:c.104C>T was not identified in this paper. The paper provides the generic framework used as the basis for the VHL VCEP specifications.Does not name this variant
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004National Society of Genetic Counselors practice guideline for cancer genetic risk assessment and counseling. NM_000551.3:c.104C>T was not identified. This is a general guideline that does not discuss individual VHL variants.Does not name this variant
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PMID 24319509 ↗Canadian guideline on genetic screening for hereditary renal cell cancers.Reaume MN et al. · 2013Canadian guideline on genetic screening for hereditary renal cell cancers. NM_000551.3:c.104C>T was not identified. The paper discusses referral criteria for hereditary RCC assessment without listing specific VHL variants.Does not name this variant
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PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG Board of Directors · 2015ACMG policy statement on updated recommendations for analysis and reporting of secondary findings in clinical genome-scale sequencing. NM_000551.3:c.104C>T was not identified. This policy document does not discuss individual variants.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional VersiPDQ cancer genetics risk assessment and counseling summary (Health Professional Version). NM_000551.3:c.104C>T was not identified. This is a clinical summary resource that does not enumerate individual VHL variants.Does not name this variant
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PMID 26389510 ↗Genetics of Renal Cell Carcinoma (PDQ®): Health Professional Version.PDQ genetics of renal cell carcinoma summary (Health Professional Version). NM_000551.3:c.104C>T was not identified. This is a clinical summary resource that does not enumerate individual VHL variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
16 / 1,544,318 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
3 Uncertain significance
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/526678/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-10183635-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-10141951-C-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-10141951-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000551.3%3Ac.104C…
- OncoKB ↗www.oncokb.org/gene/VHL/A35V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=VHL+c.104C%3ET
- 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= 1.03606e-05; MAF= 0.00104%, 16/1544318 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000179229; MAF= 0.01792%, 15/83692 alleles, homozygotes = 0); grpmax FAF= 0.0001103.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 6.78444e-06; MAF= 0.00068%, 1/147396 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 4.47307e-05; MAF= 0.00447%, 1/22356 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 526678)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.307. BayesDel score = -0.264275.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.