rs1553619976

Positions:

• chr3-10146593-C-CA

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The NM_000551.4(VHL):c.422dup (p.Asn141fs) is a frameshift variant affecting position 141. This variant is not expected to undergo nonsense mediated decay, but is in a functional domain critical to the protein function (nuclear export domain) (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Two commercial laboratories report cases. Case 1 (0.5 points): displayed bilateral renal masses and likely pheochromocytoma, with a small Paraganglioma panel run. Case 2 (0.5): Multiple renal tumors in 40s, no other family history known, and a 13-gene panel was run for renal cancers (PS4_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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/CA16611276/MONDO:0008667/078

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:3
• Conservation: PhyloP100: 4.19

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]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.422dup	p.Asn141LysfsTer3	frameshift_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3192dup		intron_variant
VHL	NM_198156.3	c.341-3192dup		intron_variant
VHL	NR_176335.1	n.751dup		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.422dup	p.Asn141LysfsTer3	frameshift_variant	2/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen VHL Variant Curation Expert Panel, ClinGen

Jun 25, 2024

The NM_000551.4(VHL):c.422dup (p.Asn141fs) is a frameshift variant affecting position 141. This variant is not expected to undergo nonsense mediated decay, but is in a functional domain critical to the protein function (nuclear export domain) (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). Two commercial laboratories report cases. Case 1 (0.5 points): displayed bilateral renal masses and likely pheochromocytoma, with a small Paraganglioma panel run. Case 2 (0.5): Multiple renal tumors in 40s, no other family history known, and a 13-gene panel was run for renal cancers (PS4_Supporting). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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

Apr 01, 2016

This truncation deletes the VHL elongin binding domain encoded by exon 3 (PMID: 14987375). This domain is required for protein stability and tumor suppressive activity (PMID: 10900011). Deletions of exon 3 have been reported in multiple families with von Hippel-Landau Syndrome (PMID: 19280651, 8069305, 8707293). For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a VHL-related disease. This sequence change inserts 1 nucleotide in exon 2 of the VHL mRNA (c.422dupA), causing a frameshift at codon 141. This creates a premature translational stop signal within the last 15 amino acids of the penultimate exon of the VHL mRNA (p.Asn141Lysfs*3). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated VHL protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2016

The c.422dupA variant, located in coding exon 2 of the VHL gene, results from a duplication of A at nucleotide position 422, causing a translational frameshift with a predicted alternate stop codon (p.N141Kfs*3). 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

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1553619976; hg19: chr3-10188277;