NM_000551.3:c.104C>T

VHL · NP_000542.1:p.(Ala35Val) · NM_000551.3

GRCh37: chr3:10183635 C>T · GRCh38: chr3:10141951 C>T

Gene: VHL Transcript: NM_000551.3

Final call

Likely Benign

BS1 strong BP4 supporting

Variant details

Gene

VHL

Transcript

NM_000551.3

Protein

NP_000542.1:p.(Ala35Val)

gnomAD AF

1.0360560454517787e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Rule18 in the ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1.0 v1.1.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

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 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.
PS1	Not met	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.
PS2	Not met	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.
PS3	Not met	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.
PS4	Not met	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.	clinvar
PS5	Not met	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.	clinvar
PM1	Not met	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.
PM2	Not met	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.	gnomad_v4
PM5	Not met	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.
PM6	Not met	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.
PP1	Not met	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.
PP2	N/A	Per 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.'	cspec
PP3	Not met	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.	revel bayesdel spliceai
PP4	N/A	Per 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.	cspec
PP5	N/A	Per 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.	cspec clinvar
BA1	Not met	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.	gnomad_v4
BS1	Met	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.	gnomad_v4 gnomad_v2
BS2	Not met	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.
BS3	Not met	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.
BS4	Not met	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.
BP1	N/A	Per 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.'	cspec
BP2	Not met	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.
BP4	Met	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.	spliceai
BP5	Not met	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.
BP6	N/A	Per VHL VCEP v1.1.0, BP6 is not applicable. The ClinGen Sequence Variant Interpretation VCEP Review Committee recommends this criterion not be used.	cspec
BP7	Not met	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.	cspec
BP3	N/A	Skipped 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).
PM3	N/A	VHL 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.'
PM4	N/A	PM4 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.

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