NM_000551.4:c.583C>T

Variant names:

• chr3-10149906-C-T
• rs5030825
• NM_000551.4:c.583C>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The NM_000551.3(VHL):c.583C>T (p.Gln195Ter) variant in VHL is a truncating mutation that terminates the VHL protein at position 195, which resides in the second Beta domain (PVS1). A total of 13 probands or families have been identified with this variant, and they have clinical features of VHL (some Type 1, some Type 2A). 11 probands or families were identified in the following PMIDs: 20660572, 8707293, 23298237, 21463266, 9408111, 17661816, 25867206, 17024664. CIViC EIDs (https://civicdb.org) are: 5472, 5360, 5691, 8693, 9255, 5097, 6623, 5134. Two additional affected cases were contributed by a commercial laboratory, with VHL phenotypes and one case has segregation data. The case total of 13 equates to moderate evidence (PS4_Moderate). 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/CA70052558/MONDO:0008667/078

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 stop_gained
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: -0.273

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]

ENSG00000287086 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 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 rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.583C>T	p.Gln195*	stop_gained	Exon 3 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.460C>T	p.Gln154*	stop_gained	Exon 2 of 2		NP_937799.1
VHL	NM_001354723.2	c.*137C>T		3_prime_UTR_variant	Exon 3 of 3		NP_001341652.1
VHL	NR_176335.1	n.912C>T		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.583C>T	p.Gln195*	stop_gained	Exon 3 of 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:4

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

-

CIViC knowledgebase, Washington University School of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

VHL nonsense variant Q195* (c.583C>T) is pathogenic for Von Hippel Landau Disease. VHL variant Q195* (c.583C>T) introduces an early stop codon resulting in a truncated protein. Loss of function VHL variants have been implicated with pathogenicity for Von Hippel Landau disease (PVS1), and this variant has been observed in patients with symptoms and family history highly characteristic of Von Hippel Landau disease (PP4). The variant does not appear in the gnomAD population database (PM2). -

Jun 25, 2024

ClinGen VHL Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000551.3(VHL):c.583C>T (p.Gln195Ter) variant in VHL is a truncating mutation that terminates the VHL protein at position 195, which resides in the second Beta domain (PVS1). A total of 13 probands or families have been identified with this variant, and they have clinical features of VHL (some Type 1, some Type 2A). 11 probands or families were identified in the following PMIDs: 20660572, 8707293, 23298237, 21463266, 9408111, 17661816, 25867206, 17024664. CIViC EIDs (https://civicdb.org) are: 5472, 5360, 5691, 8693, 9255, 5097, 6623, 5134. Two additional affected cases were contributed by a commercial laboratory, with VHL phenotypes and one case has segregation data. The case total of 13 equates to moderate evidence (PS4_Moderate). 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). -

Jun 06, 2023

Laboratory of Molecular and Cytogenetics, Department of Anatomy, All India Institute of Medical Sciences (AIIMS)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Oct 23, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q195* pathogenic mutation (also known as c.583C>T), located in coding exon 3 of the VHL gene, results from a C to T substitution at nucleotide position 583. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This pathogenic mutation has been reported in numerous families diagnosed with von Hippel-Lindau (VHL) syndrome (Crossey PA et al. Hum Mol Genet. 1994 Aug;3(8):1303-8; Hes FJ et al. Clin Genet. 2007 Aug;72(2):122-9; Losonczy G et al. BMC Med Genet. 2013 Jan 8;14:3). This mutation has also been reported in one individual diagnosed with a nonsyndromic pheochromocytoma (Neumann HP et al. N Engl J Med. 2002 May 9;346(19):1459-66). Note that this alteration is also referred to as c.796C>T in published literature. This alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	35
DANN	Uncertain	0.98
Eigen	Uncertain	0.21
Eigen_PC	Benign	-0.090
FATHMM_MKL	Benign	0.063	N
Vest4		0.72
GERP RS		0.47
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs5030825; hg19: chr3-10191590; COSMIC: COSV56548498;