chr3-10149909-A-T

Position:

• chr3-10149909-A-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PS4_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000551.3(VHL):c.586A>T (p.Lys196Ter) variant in VHL is a truncating mutation that terminates the VHL protein at position 196, which resides in the second Beta domain (PVS1). One proband has been identified with this variant, and has a family history of VHL and clinical features of VHL (CNS hemangioblastoma, renal cell carcinoma in a female of reported age 17 (Hwang et al (PMID:25078357)). One case meeting Danish VHL criteria equates to supporting evidence (PS4_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020507/MONDO:0008667/078

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 5.47

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.586A>T	p.Lys196*	stop_gained	3/3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.463A>T	p.Lys155*	stop_gained	2/2		NP_937799.1
VHL	NM_001354723.2	c.*140A>T		3_prime_UTR_variant	3/3		NP_001341652.1
VHL	NR_176335.1	n.915A>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.586A>T	p.Lys196*	stop_gained	3/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Nov 12, 2021	PVS1, PM2, PS4_Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 04, 2016	- -
Pathogenic, reviewed by expert panel	curation	ClinGen VHL Variant Curation Expert Panel, ClinGen	Jun 25, 2024	The NM_000551.3(VHL):c.586A>T (p.Lys196Ter) variant in VHL is a truncating mutation that terminates the VHL protein at position 196, which resides in the second Beta domain (PVS1). One proband has been identified with this variant, and has a family history of VHL and clinical features of VHL (CNS hemangioblastoma, renal cell carcinoma in a female of reported age 17 (Hwang et al (PMID:25078357)). One case meeting Danish VHL criteria equates to supporting evidence (PS4_Supporting). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). -

Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

This sequence change creates a premature translational stop signal (p.Lys196*) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 18 amino acid(s) of the VHL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 19333546). ClinVar contains an entry for this variant (Variation ID: 196284). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts a region of the VHL protein in which other variant(s) (p.Leu198Pro) have been determined to be pathogenic (PMID: 24555745, 27539324, 29124493). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 11, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.89
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs281860296; hg19: chr3-10191593; COSMIC: COSV56543590;