LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-11-03
Case ID: NM_000551.4_c.500G_A_20261103_011543
Framework: ACMG/AMP 2015
Variant classification summary

NM_000551.4:c.500G>A

VHL  · NP_000542.1:p.(Arg167Gln)  · NM_000551.4
GRCh37: chr3:10191507 G>A  ·  GRCh38: chr3:10149823 G>A
Gene: VHL Transcript: NM_000551.4
Final call
Pathogenic
PS1 strong PS3 supporting PS4 moderate PM1 moderate PM2 supporting PP3 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
VHL
Transcript
NM_000551.4
Protein
NP_000542.1:p.(Arg167Gln)
gnomAD AF
3.9771868561928774e-06 (v2.1)
ClinVar
Pathogenic
OncoKB
Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
Pathogenic: PS1 (strong) reflects ClinGen VHL VCEP Pathogenic interpretation of exact p.Arg167Gln.
2
Pathogenic: PS4 (moderate) reflects approximately 3.75 VCEP proband points from 15 reported carriers.
3
Pathogenic: PM1 (moderate) reflects codon 167's documented VHL germline-hotspot status.
4
Pathogenic: PS3 (supporting) reflects impaired Elongin C interaction, HIF2a regulation, and fibronectin deposition for R167Q.
5
Pathogenic: PM2 (supporting) reflects absence from gnomAD v4.1.
6
Pathogenic: PP3 (supporting) reflects a REVEL score of 0.874, above the VCEP threshold.
Final determination: Under Rule7 of the ClinGen VHL Expert Panel Version 1.1 framework, one strong criterion, two moderate criteria, and at least two supporting criteria yield a Pathogenic classification.
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: c.500G>A is a missense change, p.Arg167Gln, rather than a truncating or canonical exon-skipping variant covered by the VCEP PVS1 rule.
cspec pvs1_variant_assessment
PS1 Met Met, strong: ClinGen VHL VCEP has interpreted the exact p.Arg167Gln variant as Pathogenic.
cspec clinvar
PS2 Not assessed Not assessed: no documented de novo proband, parental testing, maternity/paternity, or VCEP-defined Danish-criteria phenotype is available for c.500G>A.
cspec PMID:10567493 PMID:10761708 PMID:12000816 PMID:12624160 PMID:15300849 PMID:17024664
PS3 Met Met, supporting: VHL R167Q reduced Elongin C interaction, failed HIF2a regulation, and caused defective fibronectin deposition in variant-specific functional studies.
cspec vcep_vhl_functional_assay_svi_documentation PMID:15574766
PS4 Met Met at Moderate: 15 reported carriers contribute approximately 3.75 VCEP points, within the 2–4-point Moderate range, pending cohort-overlap review.
cspec PMID:10567493 PMID:10761708 PMID:12000816 PMID:12624160 PMID:15300849 PMID:17024664
PM1 Met Met, moderate: PMID:12624160 identifies codon 167 as a VHL hotspot and reports the queried Arg167Gln variant.
cspec PMID:12624160
PM2 Met Met at Supporting: the variant is absent from gnomAD v4.1, satisfying the VCEP PM2 Supporting absence criterion.
cspec gnomad_v4
PM3 N/A Not applicable: The VHL VCEP specifies autosomal dominant inheritance, so PM3 is not used for this variant.
cspec
PM4 N/A Not applicable: p.Arg167Gln is a missense substitution, not an in-frame indel or stop-loss extension specified by the VCEP PM4 rule.
cspec pvs1_variant_assessment
PM5 Not met Not met: zero same-residue pathogenic comparator variants were identified for the Arg167 position, so Grantham comparison cannot be performed.
cspec pm5_candidates
PM6 Not assessed Not assessed: reports identify R167Q in patients or families but provide no VCEP-usable assumed de novo status or maternity/paternity evidence.
cspec PMID:10567493 PMID:10761708 PMID:12000816 PMID:12624160 PMID:15300849
PP1 Not assessed Not assessed: multiple reports mention R167Q, but no variant-specific affected segregation or countable informative meioses are provided.
cspec PMID:10761708 PMID:12624160 PMID:15300849
PP2 N/A Not applicable: the VHL VCEP explicitly marks PP2 as not applicable.
cspec
PP3 Met Met: REVEL score 0.874 meets the VHL VCEP PP3 missense threshold of >=0.664.
cspec revel
PP4 N/A Not applicable: the VHL VCEP explicitly designates PP4 as not applicable.
cspec
PP5 Met Not applicable: the VHL VCEP prohibits use of PP5 under its specification.
cspec clinvar
BA1 Not met Not met: the variant is absent from gnomAD v4.1, so its GroupMax Filtering Allele Frequency does not reach the BA1 threshold of 0.000156.
cspec gnomad_v4
BS1 Not met Not met: the variant is absent from gnomAD v4.1, so its GroupMax Filtering Allele Frequency does not reach the BS1 threshold of 0.0000156.
cspec gnomad_v4
BS2 Not assessed Not assessed: no qualifying set of at least three variant carriers aged 65 or older with the VCEP-required phenotype and screening information is available.
cspec
BS3 Not met Not met: VHL R167Q showed reduced Elongin C interaction, failed HIF2a regulation, and defective fibronectin deposition rather than WT-like function.
cspec vcep_vhl_functional_assay_svi_documentation PMID:15574766
BS4 Not assessed Not assessed: no tested affected relative lacking R167Q is documented in one or more families.
cspec PMID:10761708 PMID:12624160 PMID:15300849
BP1 N/A Not applicable: the VHL VCEP explicitly marks BP1 as not applicable.
cspec
BP2 Not assessed Not assessed: No phase-confirmed trans/cis observation, homozygous unaffected individual, or three pathogenic VHL variants in cis/unknown phase is documented.
cspec PMID:10567493 PMID:10761708 PMID:12000816 PMID:12624160 PMID:15300849 PMID:17024664
BP3 N/A Not applicable: p.Arg167Gln is at amino acid 167, outside the VCEP-defined 8x GXEEX repeat motif at AA14-AA48.
cspec pvs1_variant_assessment
BP4 Not assessed Not assessed: SpliceAI max delta 0.026 meets <=0.1, but the required VarSeak Class 1 or 2 result is unavailable.
cspec spliceai
BP5 Not assessed Not assessed: no evidence documents at least two qualifying co-occurrences with another highly penetrant pathogenic gene variant.
cspec
BP6 N/A Not applicable: the VHL VCEP prohibits use of BP6 under its specification.
cspec
BP7 N/A Not applicable: c.500G>A is a missense variant, whereas VHL BP7 is limited to silent or intronic variants.
cspec
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