Variant classification summary

NM_000551.4:c.541G>A

VHL · NP_000542.1:p.(Val181Ile) · NM_000551.4

GRCh37: chr3:10191548 G>A · GRCh38: chr3:10149864 G>A

Gene: VHL Transcript: NM_000551.4

Final call

VUS

PM1 moderate

Variant details

Gene

VHL

Transcript

NM_000551.4

Protein

NP_000542.1:p.(Val181Ile)

gnomAD AF

3.0975364672968294e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM1 (Moderate): p.Val181Ile lies in the pVHL alpha domain (residues 156-192), a key functional domain for Elongin C binding.

2

Final classification: VUS, as the lone PM1 moderate criterion satisfies no VHL VCEP v1.1 criteria-combination rule.

Final determination: No VHL VCEP mainRule matched a single PM1_Moderate; minimum moderate-only pathway (Rule13) needs >=3 moderate criteria.

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	Not applicable: this is a missense substitution, not a null-variant class (nonsense, frameshift, splice-site disruption, or deletion).	cspec
PS1	Not met	Not met: ClinVar classifies p.(Val181Ile) itself as uncertain significance, with no VCEP-based pathogenic interpretation of the identical change.	cspec clinvar
PS2	Not assessed	Not assessed: no de novo observation, parental confirmation, or family history is documented, so PS2 cannot be assigned.	cspec
PS3	Not assessed	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	Not assessed: no scored probands, phenotype details, or case-control enrichment data are available for p.(Val181Ile).	cspec PMID:18195360
PM1	Met	Met (Moderate): codon 181 lies in the pVHL alpha domain (residues 156-192), a key functional domain for Elongin C binding.	cspec
PM2	Not met	Not met: gnomAD v4 GroupMax FAF is 3.65e-06 (0.000365%), exceeding the permitted PM2 threshold of 0.000156%.	cspec gnomad_v4
PM3	N/A	Not applicable: the VHL Expert Panel specification designates PM3 as not applicable for this gene.	cspec
PM4	N/A	Not applicable: PM4 applies only to in-frame indels and stop-loss variants, but this missense change does not alter protein length.	cspec
PM5	Not assessed	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.	pm5_candidates cspec
PM6	Not assessed	Not assessed: no de novo proband or parental-testing result is documented to support a de novo score.	cspec
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or phenotype-confirmed segregation data are documented.	cspec
PP2	N/A	Not applicable: the VHL Expert Panel specification marks PP2 as not applicable for this gene.	cspec
PP3	Not met	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.	revel spliceai cspec
PP4	N/A	Not applicable: the VHL Expert Panel specification designates PP4 as not applicable for this gene.	cspec
PP5	N/A	Not applicable: the ClinVar record has no expert-panel submission, only non-expert laboratory assertions.	cspec clinvar
BA1	Not met	Not met: gnomAD GroupMax FAF 3.65e-06 (0.000365%) is far below the BA1 threshold of 0.0156%.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD GroupMax FAF 3.65e-06 (0.000365%) is below the BS1 threshold of 0.00156%.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no three eligible carriers aged 65 or older with absence of VHL-related cancers are documented.	cspec gnomad_v4
BS3	Not assessed	Not assessed: no VCEP-accepted functional assay data exist; only a computational stability simulation (PMID:18195360) is available.
BS4	Not assessed	Not assessed: no affected relatives lacking the variant or fully phenotyped unaffected carriers are documented for non-segregation.	cspec
BP1	N/A	Not applicable: the VHL Expert Panel specification marks BP1 as not applicable for this gene.	cspec
BP2	Not assessed	Not assessed: no phase-confirmed trans or cis observations with a pathogenic VHL variant, or qualifying homozygous observation, are documented.	cspec
BP3	N/A	Not applicable: BP3 applies only to in-frame indels in the N-terminal GXEEX repeat (residues 14-48); this is a missense at codon 181.	cspec
BP4	Not assessed	Not assessed: SpliceAI max delta 0.014 meets its threshold, but no VarSeak result exists to confirm the required two-tool concordance.	spliceai cspec
BP5	Not assessed	Not assessed: no qualifying co-occurrence with a pathogenic variant in another highly penetrant gene is documented.	cspec
BP6	N/A	Not applicable: the only likely-benign assertion comes from a single non-expert laboratory, with no expert-panel benign submission.	cspec clinvar
BP7	N/A	Not applicable: BP7 applies only to synonymous or intronic variants, and this is a missense change.	cspec

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