Classification rationale

PM1 VUS

VHL c.541G>A missense · exon 3

PM1 (Moderate): p.Val181Ile lies in the pVHL alpha domain (residues 156-192), a key functional domain for Elongin C binding. Final classification: VUS, as the lone PM1 moderate criterion satisfies no VHL VCEP v1.1 criteria-combination rule.

PM1 → VUS

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.

Gene diagram · NM_000551.4 · variants mapped to exon structure

VHL NM_000551.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

PM1 moderate review Pathogenic

Met (Moderate): codon 181 lies in the pVHL alpha domain (residues 156-192), a key functional domain for Elongin C binding.

VHL VCEP v1.1 PM1 rule: 'Putative missense variants that are known germline hotspots AND/OR in key functional domains AND/OR somatic variants that have >=10 instances for the same AA in cancerhotspots.org.'VHL VCEP v1.1 domain definitions (cited under PM4/PVS1 sections of the same specification): Alpha (α) domain spans AA 155/156-192 and mediates Elongin C binding, a function critical for VBC complex (VHL-Elongin B-Elongin C-Cullin2-RBX1) assembly; codon 181 (Val181) lies within this alpha domain.cancerhotspots.org query 'VHL V181' returned search_status 'no_result' / found=false, with evidence_sentence: 'This variant does not lie in a statistically significant hotspot.'

cspec ↗

Assessed · not applied · 5 not met · 12 not assessed

Pathogenic

PS1 Not met: ClinVar classifies p.(Val181Ile) itself as uncertain significance, with no VCEP-based pathogenic interpretation of the identical change.

PS2 Not assessed: no de novo observation, parental confirmation, or family history is documented, so PS2 cannot be assigned.

PS3 Not assessed: only an in-silico molecular-dynamics simulation (PMID:18195360) exists; no VCEP-accepted functional assay (HIF degradation, VBC stability, ECM/fibronectin binding) is available.

PS4 Not assessed: no scored probands, phenotype details, or case-control enrichment data are available for p.(Val181Ile).

PM2 Not met: gnomAD v4 GroupMax FAF is 3.65e-06 (0.000365%), exceeding the permitted PM2 threshold of 0.000156%.

PM5 Not assessed, flagged for human review: no alternate V181 missense with an established pathogenic classification was confirmed, and the ClinVar comparator search did not complete.

PM6 Not assessed: no de novo proband or parental-testing result is documented to support a de novo score.

PP1 Not assessed: no affected relatives, informative meioses, or phenotype-confirmed segregation data are documented.

PP3 Not met: REVEL scores 0.431, below the required 0.664 threshold, and SpliceAI max delta is 0.014 versus the 0.5 splice threshold.

Benign

BA1 Not met: gnomAD GroupMax FAF 3.65e-06 (0.000365%) is far below the BA1 threshold of 0.0156%.

BS1 Not met: gnomAD GroupMax FAF 3.65e-06 (0.000365%) is below the BS1 threshold of 0.00156%.

BS2 Not assessed: no three eligible carriers aged 65 or older with absence of VHL-related cancers are documented.

BS3 Not assessed: no VCEP-accepted functional assay data exist; only a computational stability simulation (PMID:18195360) is available.

BS4 Not assessed: no affected relatives lacking the variant or fully phenotyped unaffected carriers are documented for non-segregation.

BP2 Not assessed: no phase-confirmed trans or cis observations with a pathogenic VHL variant, or qualifying homozygous observation, are documented.

BP4 Not assessed: SpliceAI max delta 0.014 meets its threshold, but no VarSeak result exists to confirm the required two-tool concordance.

BP5 Not assessed: no qualifying co-occurrence with a pathogenic variant in another highly penetrant gene is documented.

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

This variant is present in gnomAD v4.1 (AF= 3.09754e-06; MAF= 0.00031%, 5/1614186 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19597e-05; MAF= 0.00220%, 2/91076 alleles, homozygotes = 0); grpmax FAF= 3.65e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 3.97744e-06; MAF= 0.00040%, 1/251418 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26669e-05; MAF= 0.00327%, 1/30612 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00031% · 5 / 1,614,186
0 hom · FAF 0.00037%

South Asian 2 / 91,076	0.0022%
African/African American 1 / 75,054	0.0013%
European (non-Finnish) 2 / 1,180,032	0.00017%

+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)

gnomAD v2.1

0.0004% · 1 / 251,418
0 hom

South Asian

1 / 30,612

0.0033%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Uncertain Significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 238111)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.431. BayesDel score = 0.0210198.

SpliceAI ↗

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56543552, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

18195360 ↗ Allosteric effects in the marginally stable von Hippel-Lindau tumor suppressor protein and allostery-based rescue mutant design. CLINVAR

24319509 ↗ Canadian guideline on genetic screening for hereditary renal cell cancers. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting 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

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint co CLINVAR

27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite CLINVAR

34012068 ↗ ACMG SF v3.0 list for reporting of secondary findings in clinical exome and geno CLINVAR

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