VHL

Final classification

Likely Pathogenic

VHL c.445G>T · p.Ala149Ser

VHL

Gene

VHL

Transcript

NM_000551.3

HGVS · transcript:coding

NM_000551.3:c.445G>T

Consequence

N/A

GRCh38

chr3:10146618 G>T

GRCh37

chr3:10188302 G>T

Basis ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1.0 v1.1.0 criteria-combination framework: matched Rule11 (1 Pathogenic.Strong + 1 Pathogenic.Moderate) with applied criteria: PS4 moderate, PM2 supporting, PP1 strong, PP3 supporting; maps to Likely Pathogenic. ▾

ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.1.0 v1.1.0 criteria-combination framework: matched Rule11 (1 Pathogenic.Strong + 1 Pathogenic.Moderate) with applied criteria: PS4 moderate, PM2 supporting, PP1 strong, PP3 supporting; maps to Likely Pathogenic.

Classification rationale

PS4PM2PP1PP3 Likely Pathogenic

VHL c.445G>T

NM_000551.3:c.445G>T (p.Ala149Ser) co-segregates with VHL disease across >7 meioses in two independent multigenerational families with VHL type 2A (PMID:9435426) and type 2B (PMID:23673869) phenotypes, meeting PP1_Strong per VHL VCEP v1.1.0.¹ The variant has been observed in multiple probands with Danish Criteria-meeting VHL phenotypes across two independent families, including pheochromocytoma, renal cell carcinoma, retinal angiomas, spinal hemangioblastoma, and pancreatic neuroendocrine tumors, meeting PS4_Moderate per VHL VCEP.² NM_000551.3:c.445G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting per VHL VCEP (threshold: absent or <=0.00000156 GroupMax FAF).³ REVEL in silico score of 0.896 exceeds the VHL VCEP PP3 threshold of >=0.664, supporting a deleterious effect of the p.Ala149Ser substitution.⁴ Applying VHL VCEP v1.1.0 combination rules: PP1_Strong (1 strong) + PS4_Moderate (1 moderate) + PM2_Supporting + PP3 (>=2 supporting) satisfies Rule 12 (1 Strong + >=2 Supporting), resulting in a classification of Likely Pathogenic.⁵

PS4 + PM2 + PP1 + PP3 → Likely Pathogenic

1 PMID:9435426 ↗PMID:23673869 ↗

2 PMID:9435426 ↗PMID:23673869 ↗clinvar ↗

3 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

4 revel

5 vcep_vhl_functional_assay_svi_documentation

Gene diagram · NM_000551.3 · variants mapped to exon structure

VHL NM_000551.3

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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 Pathogenic (5 clinical laboratories). (ClinVarID = 127829)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.14). REVEL score = 0.896. BayesDel score = 0.509578.

SpliceAI ↗

Functional Likely Oncogenic

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 not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & References.

Clinical presentation of Von Hippel Lindau syndrome type 2B associated with VHL p.A149S mutation in a large Turkish family.

PMID 23673869 ↗ · Mete T et al. · 2014 Feb CLINVAR · case observation

Searched

c.445G>Tp.A149SA149S445G

Found

Heterozygous c.445G>T (p.Ala149S) mutation was identified in all 10 symptomatic patients and 7 asymptomatic family members (aged 2-50 years) in a 3-generation Turkish family with VHL syndrome type 2B. Manifestations included pheochromocytoma (9/10), renal cell carcinoma (4/10), retinal angioma (1/10), spinal hemangioblastoma (1/10), and pancreatic neuroendocrine tumors (3/10). One asymptomatic 15-year-old carrier later developed bilateral pheochromocytoma during follow-up.

Variant

✓ Names this variant — characterised directly

Applied to

→PP1 supports · met →PS4 supports · met

Why

Variant confirmed as disease-causing in a VHL type 2B family; segregation data support PP1_Strong across multiple meioses and proband counts contribute to PS4_Moderate.

The analyzes showed heterozygous transversion from guanine to thymine at base position 445 of the coding region (c.445G > T), causing p.A149S mutation

Location Abstract; Results (DNA sequence analysis); Table 2; Figure 2 · Context PCR amplification and Sanger sequencing of VHL gene from peripheral blood; 49 family members screened · full text

Pheochromocytoma in von Hippel-Lindau disease: clinical presentation and mutation analysis in a large, multigenerational kindred.

PMID 9435426 ↗ · Atuk NO et al. · 1998 Jan CLINVAR · segregation

Searched

c.445G>Tp.Ala149SerA149Snucleotide 658

Found

G to T transversion at nucleotide 658 (NM_000551.3:c.445G>T), resulting in p.Ala149Ser, was identified as the causative mutation in a large 4-generation American kindred with VHL type 2A. Twenty-five affected members were followed; 17 developed pheochromocytoma (mean age at diagnosis 19.9 years), 18 had retinal angiomas. The mutation was confirmed in 7 affected members and 4 asymptomatic children under age 10, demonstrating complete segregation with disease.

Variant

✓ Names this variant — characterised directly

Applied to

→PP1 supports · met →PS4 supports · met

Why

Variant confirmed as disease-causing in a VHL type 2A kindred; segregation data support PP1_Strong and proband counts contribute to PS4_Moderate.

this mutation is a G to T change at nucleotide 658 that results in the substitution of a serine for an alanine residue at position 149 of the polypeptide chain

Location Abstract; Results (DNA sequence analysis); Table 3 · Context DNA sequence analysis from peripheral blood leukocytes; pedigree analysis of 4-generation kindred · full text

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

14636579 ↗ Tumorigenic mutations in VHL disrupt folding in vivo by interfering with chaperonin binding. ONCOKB

23318261 ↗ Proteostasis modulators prolong missense VHL protein activity and halt tumor progression. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

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

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR