Variant classification summary

NM_000551.3:c.434A>T

VHL · NP_000542.1:p.(Gln145Leu) · NM_000551.3

GRCh37: chr3:10188291 A>T · GRCh38: chr3:10146607 A>T

Gene: VHL Transcript: NM_000551.3

Final call

VUS

PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

VHL

Transcript

NM_000551.3

Protein

NP_000542.1:p.(Gln145Leu)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000551.3:c.434A>T (p.Gln145Leu) is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).

2

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).

3

REVEL in silico prediction score is 0.86, exceeding the VHL VCEP threshold of ≥0.664 for pathogenic prediction (PP3).

4

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.

5

This variant has been reported once in ClinVar as Uncertain Significance (VCV000219929, criteria provided, single submitter) and is absent from COSMIC and cancerhotspots.org.

6

SpliceAI predicts no splicing impact (max delta score 0.00), consistent with a missense mechanism of pathogenicity rather than aberrant splicing.

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1 v1.1 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 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.
PS1	Not met	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.
PS2	Not met	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.
PS3	Not met	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.	PMID:15611064
PS4	Not met	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.	clinvar
PS5	Not met	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.
PM1	Met	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.	PMID:15611064 cspec
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Skipped 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.
PM4	N/A	Skipped per directive. PM4 applies to in-frame insertions/deletions and stop-loss variants; this is a substitution variant.
PM5	Not met	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.	PMID:15611064
PM6	Not met	No de novo occurrence data are available for this variant. PM6/PS2 requires confirmed or assumed de novo observation with VHL-specific phenotype.
PP1	Not met	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.
PP2	N/A	VHL 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.	cspec
PP3	Met	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
PP4	N/A	VHL VCEP explicitly states PP4 is not applicable.	cspec
PP5	N/A	VHL 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.	cspec clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4
BS1	Not met	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.	gnomad_v2 gnomad_v4
BS2	Not met	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).
BS3	Not met	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.	PMID:15611064
BS4	Not met	No segregation data are available. VHL VCEP BS4 requires lack of segregation in affected members of ≥2 families (strong) or 1 family (supporting).
BP1	N/A	VHL 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.	cspec
BP2	Not met	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.
BP3	N/A	Skipped per directive. BP3 applies only to in-frame deletions/insertions in repetitive regions; this is a substitution variant.
BP4	Not met	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.	spliceai PMID:15611064
BP5	Not met	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.
BP6	N/A	VHL 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.	cspec clinvar
BP7	N/A	BP7 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.

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