3-10142001-G-A

Variant names:

• chr3-10142001-G-A
• rs373068386
• NM_000551.4:c.154G>A
• VHL p.Glu52Lys

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025).

The NM_000551.4(VHL):c.154G>A (p.Glu52Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The gene VHL is a tumor suppressor gene (CancerMine: 345 TSG, 114 oncogene, 46 driver citations). The gene VHL is a known oncogene (CancerMine: 345 TSG, 114 oncogene, 46 driver citations). The gene VHL is a cancer driver gene (CancerMine: 345 TSG, 114 oncogene, 46 driver citations). The variant allele was found at a cumulative frequency of 0.0000676 (AC=107) in the gnomAD database across 1,583,178 control chromosomes, including 1 homozygote. The grpmax filtering allele frequency (95% CI) is 0.00116. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★★). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.E52*: Uncertain_significance (ClinVar VariationId 182982, 2 stars); p.E52= (synonymous): Likely_benign (ClinVar VariationId 1665243, 2 stars) The variant has been observed in cBioPortal in 1 sample across 1 study and 1 cancer type; somatic enrichment level: NONE (Observed in at most one deduplicated cBioPortal case.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000054 (1 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Benign reviewed by expert panel P:2 U:7 B:8
• Conservation: PhyloP100: 0.417
• Publications: 5 publications found

Genes affected

VHL (HGNC:12687): (von Hippel-Lindau tumor suppressor) This gene encodes a component of a ubiquitination complex. The encoded protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. In addition to oxygen-related gene expression, this protein plays a role in many other cellular processes including cilia formation, cytokine signaling, regulation of senescence, and formation of the extracellular matrix. Variants of this gene are associated with von Hippel-Lindau syndrome, pheochromocytoma, erythrocytosis, renal cell carcinoma, and cerebellar hemangioblastoma. [provided by RefSeq, Jun 2022]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen, Genomics England PanelApp
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for VHL are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 20 criteria.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VHL NM_000551.4	MANE Select	c.154G>A p.Glu52Lys	missense	Exon 1 of 3	Prot: NP_000542.1 UniProt:
	VHL NM_001354723.2		c.154G>A p.Glu52Lys	missense	Exon 1 of 3	Prot: NP_001341652.1 UniProt:
	VHL NM_198156.3		c.154G>A p.Glu52Lys	missense	Exon 1 of 2	Prot: NP_937799.1 UniProt:

VHL NM_000551.4

MANE Select

HGVSc / HGVSpc.154G>Ap.Glu52Lys

Exon rankExon 1 of 3

missense

Prot: NP_000542.1UniProt: A0A024R2F2P40337-1

VHL NM_001354723.2

HGVSc / HGVSpc.154G>Ap.Glu52Lys

Exon rankExon 1 of 3

missense

Prot: NP_001341652.1UniProt: A0A8Q3WL21

VHL NM_198156.3

HGVSc / HGVSpc.154G>Ap.Glu52Lys

Exon rankExon 1 of 2

missense

Prot: NP_937799.1UniProt: P40337-2A0A0S2Z4K1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	VHL ENST00000256474.3	TSL:1MANE Select	c.154G>A p.Glu52Lys	missense	Exon 1 of 3	Prot: ENSP00000256474.3 UniProt:
	VHL ENST00000345392.3	TSL:1	c.154G>A p.Glu52Lys	missense	Exon 1 of 2	Prot: ENSP00000344757.2 UniProt:
	VHL ENST00000477538.2	TSL:1	n.200G>A	non_coding_transcript_exon	Exon 1 of 3	Prot:

VHL ENST00000256474.3

TSL:1MANE Select

HGVSc / HGVSpc.154G>Ap.Glu52Lys

Exon rankExon 1 of 3

missense

Prot: ENSP00000256474.3UniProt: P40337-1

VHL ENST00000345392.3

TSL:1

HGVSc / HGVSpc.154G>Ap.Glu52Lys

Exon rankExon 1 of 2

missense

Prot: ENSP00000344757.2UniProt: P40337-2

VHL ENST00000477538.2

TSL:1

HGVSc / HGVSpn.200G>A

Exon rankExon 1 of 3

non_coding_transcript_exon

Prot:

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000197	AC:30	Hom:1	AN:152242	Cov:33
GnomAD2 exomes	AF: 0.0000627	AC:12	Hom:	AN:191496	Cov:
GnomAD4 exome	AF: 0.0000538	AC:77	Hom:1	AN:1430820	Cov:32
GnomAD4 genome	AF: 0.000197	AC:30	Hom:0	AN:152358	Cov:33
TOPMed (Bravo)	AF: 0.000332	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.0000968	AC:7	Hom:0	AN:72282	Cov:
Local & regional cohorts 5 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2340	Cov:
ChinaMAP Phase 1	AF: 0.0000985	AC:	Hom:	AN:	Cov:
ESP6500 (Exome Variant Server)	AF: 0.000241	AC:3	Hom:	AN:12440	Cov:
GenomeAsia100K	AF: 0.000577	AC:2	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.000700	AC:1	Hom:	AN:1504	Cov:

Showing 11 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
Epi25(Epilepsy)	0.000429	18	41944	0.000269	18	66888
SCHEMA(Schizophrenia)	0.00240	264	110016	0.00261	478	183304

Showing 2 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	4	3	Von Hippel-Lindau syndrome (7)
-	2	1	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
1	-	-	Enchondromatosis (1)
1	-	-	Hepatoblastoma (1)
-	-	1	not specified (1)
-	1	-	VHL-related disorder (1)
-	-	1	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	5.8
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	13
DANN	Benign	0.97
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.27	N
FuncVEP CTI	Benign	0.0035
GPN-Star LLR	N/A	-1.5
GPN-Star score	N/A	1.5
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.69	T
Mutation Taster	N/A	30/70	disease causing
MutationAssessor	Benign	0.55	N
PhyloP100	Benign	0.42
popEVE	Benign	-3.2
PrimateAI	Uncertain	0.70	T
PromoterAI	N/A	-0.046	Neutral
PROVEAN	Benign	-0.76	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.021	D
Sift4G	Benign	0.21	T
Varity_R	N/A	0.20
VESM-3B	Benign	-7.2

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs373068386;

hg19: chr3-10183685;

COSMIC: COSV56549582;

COSMIC: COSV56549582;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar