chr3-10142001-G-T

Variant names:

• chr3-10142001-G-T
• rs373068386
• NM_000551.4:c.154G>T
• VHL p.Glu52*

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

+10 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 10 classification points (ACMG Germline Pathogenicity v2019). PVS1PM2

The NM_000551.4(VHL):c.154G>T (p.Glu52*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant is predicted to lead to nonsense-mediated mRNA decay (NMD). The variant allele was found at a cumulative frequency of 0.0000101 (AC=16) in the gnomAD database across 1,583,062 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000197. In-silico predictor (BayesDel (noAF)) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain Significance (★★). 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 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000084 (0 hom.)
• Consequence: VHL NM_000551.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:13
• Conservation: PhyloP100: 0.417
• Publications: 6 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 ACMG Germline Pathogenicity v2019

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: Pathogenic. The variant received 10 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PVS1Null variant in LOF gene		Frameshift/stop-gained, NMD predicted, LoF disease mechanism — very strong (PVS1); Stop-gained (exon 1 of 3) at amino acid 52 of 213, predicted to trigger nonsense-mediated mRNA decay. Loss of function is a known disease mechanism for this gene.
	PM2Absent/extremely low in population databases		Very rare in gnomAD for AD/XL gene (popmax AF < threshold/10) — PM2; GnomAD popmax AF = 0.0000197 — very rare for AD+AR gene (base 0.0001, raised to 0.000226 by highest known P/LP ClinVar AF 0.000226) — PM2 moderate.

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>T p.Glu52*	stop_gained	Exon 1 of 3	Prot: NP_000542.1 UniProt:
	VHL NM_001354723.2		c.154G>T p.Glu52*	stop_gained	Exon 1 of 3	Prot: NP_001341652.1 UniProt:
	VHL NM_198156.3		c.154G>T p.Glu52*	stop_gained	Exon 1 of 2	Prot: NP_937799.1 UniProt:

VHL NM_000551.4

MANE Select

HGVSc / HGVSpc.154G>Tp.Glu52*

Exon rankExon 1 of 3

stop_gained

Prot: NP_000542.1UniProt: A0A024R2F2P40337-1

VHL NM_001354723.2

HGVSc / HGVSpc.154G>Tp.Glu52*

Exon rankExon 1 of 3

stop_gained

Prot: NP_001341652.1UniProt: A0A8Q3WL21

VHL NM_198156.3

HGVSc / HGVSpc.154G>Tp.Glu52*

Exon rankExon 1 of 2

stop_gained

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>T p.Glu52*	stop_gained	Exon 1 of 3	Prot: ENSP00000256474.3 UniProt:
	VHL ENST00000345392.3	TSL:1	c.154G>T p.Glu52*	stop_gained	Exon 1 of 2	Prot: ENSP00000344757.2 UniProt:
	VHL ENST00000477538.2	TSL:1	n.200G>T	non_coding_transcript_exon	Exon 1 of 3	Prot:

VHL ENST00000256474.3

TSL:1MANE Select

HGVSc / HGVSpc.154G>Tp.Glu52*

Exon rankExon 1 of 3

stop_gained

Prot: ENSP00000256474.3UniProt: P40337-1

VHL ENST00000345392.3

TSL:1

HGVSc / HGVSpc.154G>Tp.Glu52*

Exon rankExon 1 of 2

stop_gained

Prot: ENSP00000344757.2UniProt: P40337-2

VHL ENST00000477538.2

TSL:1

HGVSc / HGVSpn.200G>T

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: 0.0000263	AC:4	Hom:0	AN:152242	Cov:33
GnomAD2 exomes	AF: 0.0000104	AC:2	Hom:	AN:191496	Cov:
GnomAD4 exome	AF: 0.00000839	AC:12	Hom:0	AN:1430820	Cov:32
GnomAD4 genome	AF: 0.0000263	AC:4	Hom:0	AN:152242	Cov:33
TOPMed (Bravo)	AF: 0.0000604	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000111	AC:8	Hom:0	AN:72282	Cov:
Local & regional cohorts 1 source Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.000427	AC:1	Hom:0	AN:2340	Cov:

Showing 7 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000477	2	41944	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000273	3	110018	0.0000218	4	183306

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	3	-	Von Hippel-Lindau syndrome (3)
-	2	-	Chuvash polycythemia (2)
-	1	-	Diffuse midline glioma, H3 K27-altered (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not specified (1)
-	1	-	Von Hippel-Lindau syndrome;C0031511:Pheochromocytoma;C1837915:Chuvash polycythemia;CN074294:Nonpapillary renal cell carcinoma (1)
-	1	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Benign	0.15
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.51	D
GPN-Star LLR	N/A	-2.0
GPN-Star score	N/A	2.0
Mutation Taster	N/A	6/194	disease causing (fs/PTC)
PhyloP100	Benign	0.42
PromoterAI	N/A	-0.057	Neutral
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	2.1

Showing 15 of 15 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
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: COSV56551561;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar