VHLc.445G>TLikely pathogenic

Print report

Variant interpretation report

VHL c.445G>T, p.(Ala149Ser)

NM_000551.3:c.445G>T NP_000542.1:p.(Ala149Ser) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About VHL

No gene-level summary was recorded for this case.

Key facts

Condition: von Hippel-Lindau disease
Inheritance: Autosomal dominant
Evidence used: 1 strong (pathogenic) · 1 moderate (pathogenic) · 2 supporting (pathogenic)
Expert rules: ClinGen VHL VCEP v1.1.0
Other laboratories (ClinVar): 5 Pathogenic
Pipeline record: 5 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PS4 (moderate): NM_000551.3:c.445G>T (p.Ala149S) has been observed in multiple probands with VHL-defining phenotypes across two independent families. PMID:9435426 (Atuk 1998) reports 7 affected individuals with confirmed mutation in a 4-generation American kindred with pheochromocytoma and retinal angiomas (VHL type 2A). PMID:23673869 (Mete 2014) reports 10 affected patients in a 3-generation Turkish family with pheochromocytoma, renal cell carcinoma, retinal angiomas, spinal hemangioblastoma, and pancreatic neuroendocrine tumors (VHL type 2B). Phenotypes in both families meet Danish Criteria for VHL. Estimated at 2-4 proband-equivalent points per VHL VCEP scoring, consistent with PS4_Moderate.
PM2 (supporting): NM_000551.3:c.445G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Per VHL VCEP v1.1.0, PM2_Supporting is applied for variants absent from gnomAD or with GroupMax FAF <= 0.00000156 (0.000156%). Complete absence from large population databases supports pathogenicity.
PP1 (strong): NM_000551.3:c.445G>T (p.Ala149S) co-segregates with VHL disease across >7 meioses in two independent multigenerational families. PMID:9435426 (Atuk 1998): mutation confirmed in 7 affected members across 4 generations of an American kindred, with complete genotype-phenotype concordance. PMID:23673869 (Mete 2014): mutation detected in all 10 symptomatic patients and 7 asymptomatic carriers across 3 generations of a Turkish family. Combined meioses exceed 7 across >=2 families, meeting VHL VCEP threshold for PP1_Strong.
PP3 (supporting): REVEL score for NM_000551.3:c.445G>T is 0.896, which exceeds the VHL VCEP threshold of >=0.664 for PP3 application. This in silico prediction supports a deleterious effect of the p.Ala149Ser substitution on VHL protein function. SpliceAI delta score is 0.14, indicating no significant splicing impact, so the REVEL score is interpreted in the context of a missense effect.

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.

01The reasoning

How it was classified

The recorded framework is ClinGen VHL VCEP v1.1.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 4 Benign evidence criteria: 0

Pathogenic criteria applied · 4

PS4Moderate

PS4 · moderate

NM_000551.3:c.445G>T (p.Ala149S) has been observed in multiple probands with VHL-defining phenotypes across two independent families. PMID:9435426 (Atuk 1998) reports 7 affected individuals with confirmed mutation in a 4-generation American kindred with pheochromocytoma and retinal angiomas (VHL type 2A). PMID:23673869 (Mete 2014) reports 10 affected patients in a 3-generation Turkish family with pheochromocytoma, renal cell carcinoma, retinal angiomas, spinal hemangioblastoma, and pancreatic neuroendocrine tumors (VHL type 2B). Phenotypes in both families meet Danish Criteria for VHL. Estimated at 2-4 proband-equivalent points per VHL VCEP scoring, consistent with PS4_Moderate.

PM2Supporting

PM2 · supporting

NM_000551.3:c.445G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Per VHL VCEP v1.1.0, PM2_Supporting is applied for variants absent from gnomAD or with GroupMax FAF <= 0.00000156 (0.000156%). Complete absence from large population databases supports pathogenicity.

PP1Strong

PP1 · strong

NM_000551.3:c.445G>T (p.Ala149S) co-segregates with VHL disease across >7 meioses in two independent multigenerational families. PMID:9435426 (Atuk 1998): mutation confirmed in 7 affected members across 4 generations of an American kindred, with complete genotype-phenotype concordance. PMID:23673869 (Mete 2014): mutation detected in all 10 symptomatic patients and 7 asymptomatic carriers across 3 generations of a Turkish family. Combined meioses exceed 7 across >=2 families, meeting VHL VCEP threshold for PP1_Strong.

PP3Supporting

PP3 · supporting

REVEL score for NM_000551.3:c.445G>T is 0.896, which exceeds the VHL VCEP threshold of >=0.664 for PP3 application. This in silico prediction supports a deleterious effect of the p.Ala149Ser substitution on VHL protein function. SpliceAI delta score is 0.14, indicating no significant splicing impact, so the REVEL score is interpreted in the context of a missense effect.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: 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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.140 maximum delta

Recorded SpliceAI maximum delta score: 0.140. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

5 reported laboratory submissions

5 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Context only ClinVar ↗

Functional evidence

Statement recorded

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.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under ClinGen VHL VCEP v1.1.0, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 14 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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.

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).

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.

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.

Met · 4

PS4 ModerateNM_000551.3:c.445G>T (p.Ala149S) has been observed in multiple probands with VHL-defining phenotypes across two independent families. PMID:9435426 (Atuk 1998) reports 7 affected individuals with confirmed mutation in a 4-generation American kindred with pheochromocytoma and retinal angiomas (VHL type 2A). PMID:23673869 (Mete 2014) reports 10 affected patients in a 3-generation Turkish family with pheochromocytoma, renal cell carcinoma, retinal angiomas, spinal hemangioblastoma, and pancreatic neuroendocrine tumors (VHL type 2B). Phenotypes in both families meet Danish Criteria for VHL. Estimated at 2-4 proband-equivalent points per VHL VCEP scoring, consistent with PS4_Moderate. Details ▾Hide ▴

Evidence considered

7 affected individuals with confirmed A149S in American VHL type 2A kindred (PMID:9435426)
10 affected patients with confirmed A149S in Turkish VHL type 2B family (PMID:23673869)
ClinVar classification as Pathogenic by 5 clinical laboratories (Variation ID 127829)

Still missing

Exact proband scoring per VCEP PS4 phenotype point tables requires detailed review of individual phenotypes against Danish Criteria
current estimate is conservative

Sources

PMID:9435426 ↗PMID:23673869 ↗clinvar ↗

PM2 SupportingNM_000551.3:c.445G>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Per VHL VCEP v1.1.0, PM2_Supporting is applied for variants absent from gnomAD or with GroupMax FAF <= 0.00000156 (0.000156%). Complete absence from large population databases supports pathogenicity. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (exomes)
Absent from gnomAD v4.1 (exomes)
Absent from gnomAD-Canada v1.0 (genomes)

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP1 StrongNM_000551.3:c.445G>T (p.Ala149S) co-segregates with VHL disease across >7 meioses in two independent multigenerational families. PMID:9435426 (Atuk 1998): mutation confirmed in 7 affected members across 4 generations of an American kindred, with complete genotype-phenotype concordance. PMID:23673869 (Mete 2014): mutation detected in all 10 symptomatic patients and 7 asymptomatic carriers across 3 generations of a Turkish family. Combined meioses exceed 7 across >=2 families, meeting VHL VCEP threshold for PP1_Strong. Details ▾Hide ▴

Evidence considered

Mutation confirmed in 7 affected members across 4 generations of American VHL type 2A kindred (PMID:9435426)
Mutation detected in all 10 affected and 7 asymptomatic carriers across 3 generations of Turkish VHL type 2B family (PMID:23673869)
Complete genotype-phenotype concordance in both families

Sources

PMID:9435426 ↗PMID:23673869 ↗

PP3 SupportingREVEL score for NM_000551.3:c.445G>T is 0.896, which exceeds the VHL VCEP threshold of >=0.664 for PP3 application. This in silico prediction supports a deleterious effect of the p.Ala149Ser substitution on VHL protein function. SpliceAI delta score is 0.14, indicating no significant splicing impact, so the REVEL score is interpreted in the context of a missense effect. Details ▾Hide ▴

Evidence considered

REVEL score: 0.896 (VCEP threshold >=0.664)
SpliceAI max delta: 0.14 (no significant splice effect)

Sources

revelspliceai ↗

Not met · 14 · evaluated, threshold not reached

PS1 PS1 requires a different nucleotide change at the same amino acid position (Ala149) that has been classified as pathogenic by the VHL VCEP. No VCEP-classified pathogenic comparator at residue 149 with a different nucleotide change was identified. Although p.Ala149Pro (A149P) has been studied as a tumorigenic mutation (PMID:14636579), it has not been formally classified by the VHL VCEP. Details ▾Hide ▴

Still missing

No VCEP-classified pathogenic variant at residue A149 with a different nucleotide change identified

PS2 No de novo occurrence of NM_000551.3:c.445G>T with confirmed or assumed parentage was identified in the reviewed literature. The variant was observed to segregate within multigenerational families, indicating inherited rather than de novo origin. Details ▾Hide ▴

Still missing

No de novo reports identified in available literature

PS3 No variant-specific functional studies of p.Ala149Ser (NM_000551.3:c.445G>T) were identified in the available full-text literature. PMID:14636579 (Feldman 2003) characterized p.Ala149Pro (A149P) as disrupting TRiC chaperonin binding and VHL folding, but A149S was not tested. No HIF degradation, VBC complex stability, or fibronectin binding assay data were identified for this specific variant. Details ▾Hide ▴

Still missing

No functional assay data for p.Ala149S identified
functional characterization of A149S in HIF degradation or VBC complex stability assays would be informative

PM1 The variant is located at codon 149 within the Beta domain (nuclear export region, AA 114-155), which is a key functional domain, and within the TRiC chaperonin binding Box 2 (AA 148-155). However, the residue is not a statistically significant germline or somatic hotspot per cancerhotspots.org data. No COSMIC entries were found for this variant. PM1 per VHL VCEP requires the residue to be a known germline hotspot AND/OR have >=10 somatic instances in cancerhotspots.org, or <10 instances for PM1_Supporting. Neither threshold is met based on available hotspot data. Details ▾Hide ▴

Evidence considered

Residue A149 is not a statistically significant hotspot
Variant absent from COSMIC
A149 lies within the TRiC binding Box 2 (AA 148-155) and Beta domain
but hotspot criteria not met

Still missing

VHL VCEP germline and somatic hotspot residue table not available for direct lookup
hotspot assessment based on cancerhotspots.org and COSMIC data

Sources

PMID:14636579 ↗

PM5 PM5 requires a different pathogenic missense variant at the same amino acid residue (Ala149) classified by the VHL VCEP. Although p.Ala149Pro (A149P) is characterized as a tumorigenic mutation disrupting TRiC binding and VHL folding (PMID:14636579), PM5 candidate screening did not identify any VCEP-classified pathogenic comparator at residue 149. Per VHL VCEP PM5 rules, the comparator must have pathogenicity established using VHL VCEP specifications. Details ▾Hide ▴

Still missing

No VCEP-classified pathogenic missense comparator at residue A149 identified

PM6 No de novo occurrence of NM_000551.3:c.445G>T was identified in the reviewed literature. The variant was observed to segregate in multigenerational families (PMID:9435426, PMID:23673869), consistent with inherited transmission. Details ▾Hide ▴

Still missing

No de novo reports identified

BA1 NM_000551.3:c.445G>T is absent from gnomAD v2.1 and v4.1. The VHL VCEP BA1 threshold is >=0.000156 (0.0156%) GroupMax Filtering Allele Frequency. Complete absence from population databases does not meet the BA1 threshold for a stand-alone benign classification. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1
Absent from gnomAD v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 NM_000551.3:c.445G>T is absent from gnomAD v2.1 and v4.1. The VHL VCEP BS1 threshold is >=0.0000156 (0.00156%) GroupMax Filtering Allele Frequency. Complete absence from population databases does not meet the BS1 threshold for strong benign evidence. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1
Absent from gnomAD v4.1

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No evidence was identified of >=3 individuals aged >=65 years harboring NM_000551.3:c.445G>T who are unaffected with full or partial phenotyping for VHL-related cancers. The variant has only been reported in affected individuals or young asymptomatic carriers within VHL families. Details ▾Hide ▴

Still missing

No data on elderly unaffected carriers available

BS3 No benign functional evidence was identified for NM_000551.3:c.445G>T (p.Ala149Ser). No studies demonstrating normal HIF degradation, intact VBC complex stability, or preserved fibronectin binding/ECM formation were found for this specific variant. All available functional data in the literature pertain to other variants at the same residue (e.g., A149P). Details ▾Hide ▴

Still missing

No benign functional studies for A149S identified

BS4 No evidence of lack of segregation in affected family members was identified. On the contrary, the available evidence from two independent families (PMID:9435426, PMID:23673869) demonstrates strong co-segregation of NM_000551.3:c.445G>T with VHL disease phenotypes. Details ▾Hide ▴

No further detail was recorded.

BP2 No evidence was identified of NM_000551.3:c.445G>T observed in trans with a known pathogenic VHL variant, in a homozygous state in an unaffected individual, or in cis with multiple pathogenic VHL variants. Details ▾Hide ▴

Still missing

No phase or zygosity data available for this variant outside family studies

BP4 Per VHL VCEP v1.1.0, missense predictors are not to be used for BP4 assignment due to poor classification accuracy for benign VHL variants. BP4 can only be applied for splicing assessment with SpliceAI <=0.1 and VarSeak Class 1 or 2. The SpliceAI max delta score for this variant is 0.14, which exceeds the 0.1 threshold. BP4 is not met. Details ▾Hide ▴

Evidence considered

SpliceAI max delta: 0.14 (exceeds VCEP BP4 threshold of <=0.1)
VCEP prohibits use of missense predictors for BP4

Sources

spliceai ↗

BP5 No evidence was identified of NM_000551.3:c.445G>T co-occurring with a pathogenic variant in a different gene that fully explains the patient's phenotype. VHL VCEP requires two or more such co-occurrences with specific phenotype considerations. No such cases were identified in the reviewed literature. Details ▾Hide ▴

Still missing

No co-occurrence data with pathogenic variants in other genes available

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/APVS1 is not applicable to missense variants. NM_000551.3:c.445G>T is a missense substitution (p.Ala149Ser), not a null variant (nonsense, frameshift, or canonical splice). Per the VHL VCEP v1.1.0, PVS1 applies only to truncating variants after codon 54 or variants causing exon skipping. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPPP2 is not applicable per VHL VCEP v1.1.0. While VHL has known pathogenic missense variants, gnomAD shows VHL is not intolerant to missense variation (Z score = -0.39). The VCEP explicitly states: 'Do not use. Missense variants in VHL will need to achieve pathogenic interpretation via other evidence codes.' Details ▾Hide ▴

No further detail was recorded.

PP4 VCEPPP4 is not applicable per VHL VCEP v1.1.0. The VCEP instructs to combine phenotype data with PS4 to avoid double counting probands. Details ▾Hide ▴

No further detail was recorded.

PP5 VCEPPP5 is not applicable per VHL VCEP v1.1.0. The VCEP explicitly marks PP5 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPBP1 is not applicable per VHL VCEP v1.1.0. The VCEP states: 'This rule code does not apply to this gene, as truncating variants account for only a portion of disease-causing variants.' Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is not applicable per VHL VCEP v1.1.0. The VCEP explicitly marks BP6 as 'Not Applicable for this VCEP' per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 is not applicable to missense variants. Per VHL VCEP v1.1.0, BP7 can only be applied to silent or intronic variants where BP4 is met for lack of splice effect and PhyloP score <=0.2. NM_000551.3:c.445G>T is a missense substitution (p.Ala149Ser), not a silent or intronic variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not included in the VHL VCEP v1.1.0 criteria framework. The VCEP has elected not to use reputation-based criteria (both PP5 and PS5). The related criterion PP5 is explicitly marked as 'Not Applicable for this VCEP.' Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: VHL
Transcript: NM_000551.3
Coding (HGVS c.): NM_000551.3:c.445G>T
Protein (HGVS p.): NP_000542.1:p.(Ala149Ser)
GRCh38: chr3:10146618 G>T
GRCh37: chr3:10188302 G>T
ClinVar: 127829

Gene diagram

Every interpreted variant in VHL, mapped onto the exon structure of NM_000551.3. Select a row to find it on the plot.

VHLNM_000551.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in VHL — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -104 bp

0.140

SpliceAI acceptor gainat +19 bp

0.000

SpliceAI donor lossat +18 bp

0.070

SpliceAI donor gainat +58 bp

0.000

Pangolin splice lossmagnitude shown

-0.110

Pangolin splice gain

0.000

Other predictors

REVEL: 0.896
BayesDel: 0.510

How the predictions were used

Evidence considered

REVEL score: 0.896 (VCEP threshold >=0.664)
SpliceAI max delta: 0.14 (no significant splice effect)

Sources

revelspliceai ↗

Evidence considered

SpliceAI max delta: 0.14 (exceeds VCEP BP4 threshold of <=0.1)
VCEP prohibits use of missense predictors for BP4

Sources

spliceai ↗

No further detail was recorded.

Statement

In silico

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

8 paper records listed. 2 cited in the classification.

Cited in the classification

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

Mete T et al. · 2014 Feb

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.
→ PS4 → PP1 Names this variant
PMID 23673869 ↗
Source detail

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

Atuk NO et al. · 1998 Jan

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.
→ PS4 → PP1 Names this variant
PMID 9435426 ↗
Source detail

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

Other recorded publications

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

Characterized the TRiC/CCT chaperonin binding determinants in the VHL protein, identifying two hydrophobic beta-strand motifs (Box 1: AA 116-119; Box 2: AA 148-155). Tumor-causing mutations in Box 2 including p.Ala149Pro (A149P), p.Asn150Lys (N150K), and p.Ile151Ser (I151S) were shown to disrupt TRiC binding and lead to misfolding of newly translated VHL. p.Ala149Ser (A149S) was not specifically tested. The study established that Box 2 mutations can cause loss of function through chaperonin-mediated folding defects.
Does not name this variant
PMID 14636579 ↗
Quoted passage
several mutations, including G114R, L118P, A149P, N150K, and I151S, significantly impaired binding to TRiC
Figure 3A; Figure 4; Figure 6
Proteostasis modulators prolong missense VHL protein activity and halt tumor progression.

Yang C et al. · 2013

Investigated proteostasis modulators (Hsp90 inhibitors) that prolong missense mutant VHL protein activity and halt tumor progression. The study demonstrated that missense VHL mutants are unstable and degraded contemporaneously with translation. p.Ala149Ser was not specifically mentioned or tested among the missense mutants studied.
Does not name this variant
PMID 23318261 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.

Trepanier A et al. · 2004

National Society of Genetic Counselors practice guideline for cancer genetic risk assessment and counseling. Recommends general approaches to cancer genetic counseling including pedigree analysis, risk assessment, and testing strategies. No variant-specific data for NM_000551.3:c.445G>T or any specific VHL mutation is discussed.
Does not name this variant
PMID 15604628 ↗
Canadian guideline on genetic screening for hereditary renal cell cancers.

No paper-specific finding is recorded.

PMID 24319509 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.

ACMG policy statement providing updated recommendations for analysis and reporting of secondary findings in clinical genome-scale sequencing. Discusses general principles for reporting incidental findings including genes on the ACMG secondary findings list. No variant-specific mention of NM_000551.3:c.445G>T or VHL A149S.
Does not name this variant
PMID 25356965 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi

No paper-specific finding is recorded.

PMID 26389258 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.140 Open source ↗

ClinVar 5 Pathogenic Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories). (ClinVarID = 127829)

In silico

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

Functional

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.