About VHL
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
VHL c.434A>T, p.(Gln145Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
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. 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: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
p.Gln145 is located in the β-domain (AA 63–155) of VHL, a key functional domain identified by the VHL VCEP as critical for nuclear export and HIF-α recognition. PMID:15611064 identifies Gln145 within the L7 loop as a focal 'control node' coordinating dynamic coupling between pVHL and HIF-α, with the tumorigenic Q145H mutant abolishing correlated dynamic motions. The VCEP PM1 rule at moderate strength applies to missense variants in key functional domains.
PM2Supporting
PM2 · supporting
NM_000551.3:c.434A>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per VHL VCEP PM2_Supporting rule: variants absent from gnomAD or with GroupMax FAF ≤ 0.00000156 qualify for PM2_Supporting.
PP3Supporting
PP3 · supporting
REVEL score is 0.86, which exceeds the VHL VCEP PP3 threshold of ≥0.664 for missense variants. This in silico prediction supports a pathogenic effect of the p.Gln145Leu substitution.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1 v1.1 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate, PM2 supporting, PP3 supporting; no rule matched the adjudicated criteria.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
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
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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, with the data and sources behind each one.
29 criteria with recorded statuses: 3 met · 16 not met · 0 not assessed · 10 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.434A>T (p.Gln145Leu) is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).
Amino acid position 145 lies within the VHL β-domain (AA 63–155), a key functional domain identified by the VHL VCEP, and has been characterized as a critical 'control node' for pVHL–HIF-1α dynamic coupling (PMID:15611064) (PM1_Moderate).
REVEL in silico prediction score is 0.86, exceeding the VHL VCEP threshold of ≥0.664 for pathogenic prediction (PP3).
The sister variant p.Gln145His has been functionally demonstrated as defective in HIF-α degradation and VEC complex dynamic coupling (PMID:15611064) but has not been classified by the VHL VCEP, precluding application of PM5 under current VCEP specifications.
This variant has been reported once in ClinVar as Uncertain Significance (VCV000219929, criteria provided, single submitter) and is absent from COSMIC and cancerhotspots.org.
SpliceAI predicts no splicing impact (max delta score 0.00), consistent with a missense mechanism of pathogenicity rather than aberrant splicing.
No criteria match.
Met · 3
PM1 Moderatep.Gln145 is located in the β-domain (AA 63–155) of VHL, a key functional domain identified by the VHL VCEP as critical for nuclear export and HIF-α recognition. PMID:15611064 identifies Gln145 within the L7 loop as a focal 'control node' coordinating dynamic coupling between pVHL and HIF-α, with the tumorigenic Q145H mutant abolishing correlated dynamic motions. The VCEP PM1 rule at moderate strength applies to missense variants in key functional domains. Details ▾Hide ▴
Evidence considered
- Codon 145 lies in the β-domain (AA 63–155)
- a key functional domain per VHL VCEP PVS1 critical domain designation.
- PMID:15611064 identifies Gln145 as a critical 'control node' for dynamic coupling of pVHL–HIF-1α recognition
- Q145H disrupts this function.
Sources
PM2 SupportingNM_000551.3:c.434A>T is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Per VHL VCEP PM2_Supporting rule: variants absent from gnomAD or with GroupMax FAF ≤ 0.00000156 qualify for PM2_Supporting. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
- Absent from gnomAD-Canada v1.0.
Sources
PP3 SupportingREVEL score is 0.86, which exceeds the VHL VCEP PP3 threshold of ≥0.664 for missense variants. This in silico prediction supports a pathogenic effect of the p.Gln145Leu substitution. Details ▾Hide ▴
Evidence considered
- REVEL score 0.86 (threshold ≥0.664 per VHL VCEP).
Sources
revel
Not met · 16 · evaluated, threshold not reached
PS1 No VHL VCEP-established pathogenic variant with the identical amino acid change (p.Gln145Leu) exists. VCEP PS1 requires a prior variant with interpretation by the VHL VCEP or pathogenicity established using VHL VCEP specifications. Details ▾Hide ▴
Still missing
- No VCEP-classified pathogenic comparator with same amino acid change at codon 145.
PS2 No de novo occurrence data for NM_000551.3:c.434A>T is available. The variant has a single ClinVar submission as VUS with no de novo reports. Details ▾Hide ▴
Still missing
- No de novo proband data available.
PS3 The exact variant p.Gln145Leu has not been directly functionally tested. PMID:15611064 tested p.Gln145His (same codon, different amino acid) and demonstrated defective HIF-α degradation, loss of dynamic coupling, and inability to bind HIF-α in vivo. However, a single variant at the same codon does not constitute systematic range characterization for PS3 purposes; this evidence is more appropriately applied via PM5. Per the PS3–PM5 boundary rule: functional data for a sister variant at the same position constitutes PM5 territory unless the variant itself was directly tested or falls within a systematically characterized range. Details ▾Hide ▴
Evidence considered
- PMID:15611064 tested p.Gln145His (not p.Gln145Leu) and showed defective HIF-α degradation
- data supports codon-level pathogenicity but does not satisfy PS3 requirements for the exact variant.
Still missing
- No direct functional testing of p.Gln145Leu. Testing of Q145L in HIF-α degradation or VBC complex stability assays would be needed for PS3.
Sources
PS4 No proband count or case-control data are available. The variant has one ClinVar submission as VUS from a single clinical laboratory with no supporting phenotype data. VCEP PS4 requires proband scoring using the VHL phenotype point system; no data are available to assign points. Details ▾Hide ▴
Evidence considered
- Single ClinVar submission as VUS
- no proband phenotype data.
Still missing
- No affected proband counts or phenotype descriptions available for PS4 scoring.
Sources
PM5 A different missense at the same codon (p.Gln145His, PMID:15611064) has been functionally demonstrated as pathogenic. However, VHL VCEP PM5 requires the comparator variant to have pathogenicity 'established by interpretation of the VHL VCEP or by a variant with pathogenicity established using VHL VCEP specifications.' p.Gln145His has not been classified by the VHL VCEP, so it does not satisfy the VCEP PM5 prerequisite despite strong functional evidence. The Grantham distance of Q145L (Gln→Leu: radical, Grantham ~113) is greater than Q145H (Gln→His: moderately conservative, Grantham ~24), which would satisfy the Grantham distance criterion if a VCEP-classified comparator were available. Details ▾Hide ▴
Evidence considered
- PMID:15611064 shows Q145H is defective in HIF-α degradation
- but Q145H lacks VHL VCEP classification required for PM5 comparator.
Still missing
- Q145H has not been classified by the VHL VCEP. If Q145H were VCEP-classified as pathogenic
- PM5 would apply at moderate strength given the larger Grantham distance of Q145L.
Sources
PM6 No de novo occurrence data are available for this variant. PM6/PS2 requires confirmed or assumed de novo observation with VHL-specific phenotype. Details ▾Hide ▴
Still missing
- No de novo proband data.
PP1 No segregation data are available. VHL VCEP PP1 requires 3–4 meioses across ≥1 family for supporting strength; no family studies have been reported for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available.
BA1 The variant is absent from gnomAD v2.1 and v4.1. VHL VCEP BA1 requires GroupMax Filtering Allele Frequency ≥ 0.000156 (0.0156%). This threshold is not met. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- does not meet BA1 threshold.
Sources
BS1 The variant is absent from gnomAD v2.1 and v4.1. VHL VCEP BS1 requires GroupMax Filtering Allele Frequency ≥ 0.0000156 (0.00156%). This threshold is not met. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- does not meet BS1 threshold.
Sources
BS2 No data are available on healthy adults ≥65 years harboring this variant. VHL VCEP BS2 requires at least 3 individuals ≥65 years, unaffected, with full phenotyping for VHL-related cancers (strong) or without full phenotyping (supporting). Details ▾Hide ▴
Still missing
- No data on unaffected older adults harboring this variant.
BS3 No functional studies demonstrating a benign effect for p.Gln145Leu are available. PMID:15611064 tested p.Gln145His and demonstrated a damaging effect (defective HIF-α degradation), which argues against a benign interpretation of this codon. Details ▾Hide ▴
Evidence considered
- PMID:15611064 shows Q145H is defective in HIF-α degradation
- no benign functional data exist for this codon.
Still missing
- No functional data demonstrating normal VHL function for p.Gln145Leu.
Sources
BS4 No segregation data are available. VHL VCEP BS4 requires lack of segregation in affected members of ≥2 families (strong) or 1 family (supporting). Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 No evidence of this variant observed in trans with a known pathogenic VHL variant, in a homozygous state in an unaffected individual, or in cis with three or more pathogenic VHL variants. Details ▾Hide ▴
Still missing
- No phase data with other VHL variants.
BP4 SpliceAI max delta score is 0.00, indicating no predicted splicing impact. However, BP4 assesses 'no impact on gene or gene product.' While there is no splicing impact, the missense change p.Gln145Leu occurs at a residue identified by PMID:15611064 as a critical 'control node' for pVHL–HIF-α dynamic coupling, and the sister variant Q145H has demonstrated functional impact. The amino acid substitution itself is predicted damaging (REVEL 0.86). BP4 is therefore not met as the gene product is impacted through altered protein function. Details ▾Hide ▴
Evidence considered
- SpliceAI 0.00 indicates no splicing impact
- but the missense at a functionally critical residue (PMID:15611064) and high REVEL (0.86) indicate impact on the gene product.
Sources
BP5 No evidence of co-occurrence with a pathogenic variant in a different gene that fully explains the patient's phenotype. VHL VCEP BP5 requires two or more such co-occurrences meeting specific phenotype criteria. Details ▾Hide ▴
Still missing
- No co-occurrence data with pathogenic variants in other genes.
PS5 PS5 requires observation of the variant in trans with a known pathogenic variant, typically applied in recessive disorders. VHL is an autosomal dominant disorder; no such evidence exists for this variant. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus). NM_000551.3:c.434A>T is a missense variant (p.Gln145Leu) and does not fall into any PVS1-eligible variant class. Details ▾Hide ▴
No further detail was recorded.
PM3 VCEPSkipped per directive. PM3 applies to recessive disorders (variant in trans with pathogenic variant); VHL is autosomal dominant and VHL VCEP marks PM3 as Not Applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per directive. PM4 applies to in-frame insertions/deletions and stop-loss variants; this is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
PP2 VCEPVHL VCEP explicitly states PP2 is not applicable. While there are known pathogenic missense variants in VHL, gnomAD shows VHL is not intolerant to missense variation (Z score = −0.39); benign and common missense variants exist. Details ▾Hide ▴
Sources
PP4 VCEPVHL VCEP explicitly states PP4 is not applicable. Details ▾Hide ▴
Sources
PP5 VCEPVHL VCEP explicitly states PP5 is not applicable. Additionally, the ClinVar entry for this variant (VCV000219929) has review status 'criteria provided, single submitter' (1-star), not 'reviewed by expert panel' (3-star), so PP5 would not apply even under global PP5/BP6 override rules. Details ▾Hide ▴
BP1 VCEPVHL VCEP explicitly states 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 ▴
Sources
BP3 N/ASkipped per directive. BP3 applies only to in-frame deletions/insertions in repetitive regions; this is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP6 VCEPVHL VCEP explicitly states BP6 is not applicable. Additionally, the ClinVar entry (VCV000219929) has review status 'criteria provided, single submitter' (1-star), not 'reviewed by expert panel' (3-star), so BP6 would not apply even under global PP5/BP6 override rules. Details ▾Hide ▴
BP7 N/ABP7 applies to silent or intronic variants with no predicted splice impact and PhyloP ≤ 0.2. NM_000551.3:c.434A>T is a missense variant, not silent or intronic. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- VHL
- Transcript
- NM_000551.3
- Coding (HGVS c.)
- NM_000551.3:c.434A>T
- Protein (HGVS p.)
- NP_000542.1:p.(Gln145Leu)
- GRCh38
- chr3:10146607 A>T
- GRCh37
- chr3:10188291 A>T
- ClinVar
- 219929
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in VHL
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.860
- BayesDel
- 0.309
How the predictions were used
PP3 SupportingREVEL score is 0.86, which exceeds the VHL VCEP PP3 threshold of ≥0.664 for missense variants. This in silico prediction supports a pathogenic effect of the p.Gln145Leu substitution. Details ▾Hide ▴
Evidence considered
- REVEL score 0.86 (threshold ≥0.664 per VHL VCEP).
Sources
revel
BP4 SpliceAI max delta score is 0.00, indicating no predicted splicing impact. However, BP4 assesses 'no impact on gene or gene product.' While there is no splicing impact, the missense change p.Gln145Leu occurs at a residue identified by PMID:15611064 as a critical 'control node' for pVHL–HIF-α dynamic coupling, and the sister variant Q145H has demonstrated functional impact. The amino acid substitution itself is predicted damaging (REVEL 0.86). BP4 is therefore not met as the gene product is impacted through altered protein function. Details ▾Hide ▴
Evidence considered
- SpliceAI 0.00 indicates no splicing impact
- but the missense at a functionally critical residue (PMID:15611064) and high REVEL (0.86) indicate impact on the gene product.
Sources
BP7 N/ABP7 applies to silent or intronic variants with no predicted splice impact and PhyloP ≤ 0.2. NM_000551.3:c.434A>T is a missense variant, not silent or intronic. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.86. BayesDel score = 0.309088.
6 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
-
PMID 15611064 ↗Inactivation of VHL by tumorigenic mutations that disrupt dynamic coupling of the pVHL.hypoxia-inducible transcription factor-1alpha complex.Miller et al. (2005) investigated the role of Gln145 in pVHL–HIF-1α dynamic coupling. The tumorigenic mutant p.Gln145His (Q145H) was shown to abolish correlated dynamic motions in the pVHL–HIF-1α complex, fail to degrade HIF-2α in 786-O RCC cells, and fail to bind HIF-α in vivo despite intact VEC complex assembly. Gln145 is identified as a critical 'control node' at the α/β-domain interface. The variant p.Gln145Leu (Q145L, NM_000551.3:c.434A>T) was not specifically studied.→ PM1 Does not name this variant
Source detail
dynamic organization of pVHL·HIF-1α recognition is focally centered on Gln145 within the L7 loop, and its tumorigenic mutant Q145H abolishes almost all of the correlated dynamic motions
Location Abstract; Results (Q145H Mutant section); Figures 7, 8
Context Molecular dynamics simulations, HIF-2α degradation assay in 786-O RCC cells, in vitro hydroxylation-dependent HIF-1α binding assay, VEC complex assembly in 293T cells
Other recorded publications
-
PMID 20664475 ↗The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.Chen H et al. · 2010Consensus guideline from the North American Neuroendocrine Tumor Society on diagnosis and management of pheochromocytoma and paraganglioma. Discusses VHL syndrome as one of several hereditary syndromes associated with pheochromocytoma. NM_000551.3:c.434A>T was not identified in this paper.Does not name this variant
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Lists VHL syndrome among hereditary cancer syndromes warranting genetic counseling referral when specific criteria are met. NM_000551.3:c.434A>T was not identified in this paper.Does not name this variant
-
PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional VersiPDQ Cancer Genetics Editorial Board summary on cancer genetics risk assessment and counseling. Gene-level discussion of hereditary cancer syndromes including VHL. NM_000551.3:c.434A>T was not identified in available materials.Does not name this variant
-
PMID 27854360 ↗Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.Kalia SS et al. · 2017ACMG Secondary Findings Maintenance Working Group policy statement updating the list of genes recommended for return of secondary findings in clinical genomic sequencing (ACMG SF v2.0). VHL is listed as a gene for which known pathogenic and expected pathogenic variants should be reported. NM_000551.3:c.434A>T was not identified in this paper.Does not name this variant
-
PMID 24893135 ↗Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.Lenders JW et al. · 2014Endocrine Society clinical practice guideline on pheochromocytoma and paraganglioma. Discusses VHL as a hereditary syndrome associated with pheochromocytoma. NM_000551.3:c.434A>T 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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 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/219929/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-10188291-A-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-10146607-A-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-10146607-A-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000551.3%3Ac.434A…
- OncoKB ↗www.oncokb.org/gene/VHL/Q145L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=VHL+c.434A%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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 219929)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.86. BayesDel score = 0.309088.
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.