NM_000551.3:c.434A>T (p.Gln145Leu) is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).1 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).2 REVEL in silico prediction score is 0.86, exceeding the VHL VCEP threshold of ≥0.664 for pathogenic prediction (PP3).3 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.4 This variant has been reported once in ClinVar as Uncertain Significance (VCV000219929, criteria provided, single submitter) and is absent from COSMIC and cancerhotspots.org.5 SpliceAI predicts no splicing impact (max delta score 0.00), consistent with a missense mechanism of pathogenicity rather than aberrant splicing.6
VHL
Final classification
VUS
VHL c.434A>T · p.Gln145Leu
VHL
NM_000551.3:c.434A>T (p.Gln145Leu) is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).
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.
Classification rationale
PM1PM2PP3
VUS
VHL c.434A>T
PM1 + PM2 + PP3
→
VUS
3
revel
Gene diagram
· NM_000551.3 · variants mapped to exon structure
VHL
NM_000551.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
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.
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
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.Absent from gnomAD-Canada v1.0.
✓
PP3
supporting
Pathogenic
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.
REVEL score 0.86 (threshold ≥0.664 per VHL VCEP).
Assessed · not applied
Pathogenic
PS1
No VHL VCEP-established pathogenic variant with the identical amino acid change (p.Gln145Leu) exists.
PS2
No de novo occurrence data for NM_000551.3:c.434A>T is available.
PS3
The exact variant p.Gln145Leu has not been directly functionally tested.
PS4
No proband count or case-control data are available.
PM5
A different missense at the same codon (p.Gln145His, PMID:15611064) has been functionally demonstrated as pathogenic.
PM6
No de novo occurrence data are available for this variant.
PP1
No segregation data are available.
Benign
BA1
The variant is absent from gnomAD v2.1 and v4.1.
BS1
The variant is absent from gnomAD v2.1 and v4.1.
BS2
No data are available on healthy adults ≥65 years harboring this variant.
BS3
No functional studies demonstrating a benign effect for p.Gln145Leu are available.
BS4
No segregation data are 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.
BP4
SpliceAI max delta score is 0.00, indicating no predicted splicing impact.
BP5
No evidence of co-occurrence with a pathogenic variant in a different gene that fully explains the patient's phenotype.
N/A · 10
PVS1 · PM3 · PM4 · PP2 · PP4 · PP5 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & References.
Inactivation of VHL by tumorigenic mutations that disrupt dynamic coupling of the pVHL.hypoxia-inducible transcription factor-1alpha complex.
Searched
c.434A>TGln145LeuQ145LQ145HGln145145
Found
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.
Variant
◇ Residue / gene-level — variant not named
Applied to
→PM1 supports · met
Why
Q145H functional data supports codon-level pathogenicity and the critical functional role of Gln145. Used to support PM1 (key functional domain) but does not independently meet PS3 threshold for Q145L. PM5 not applicable because Q145H lacks VHL VCEP classification.
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 · full text
Sources & reference links
9Sources
Triaged references · 5 PMIDs not cited in assessment
20664475 ↗
The North American Neuroendocrine Tumor Society consensus guideline for the diagnosis and management of neuroendocrine tumors: pheochromocytoma, paraganglioma, and medullary thyroid cancer.
CLINVAR
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.
CLINVAR
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.
CLINVAR
24893135 ↗
Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline.
CLINVAR