rs5030622

chr3-10149809-C-Achr3-10149809-C-Gchr3-10149809-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000551.4(VHL):c.486C>A(p.Cys162Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.16

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 18 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 93 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10149809-C-A is Pathogenic according to our data. Variant chr3-10149809-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 223226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10149809-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.486C>A	p.Cys162Ter	stop_gained	3/3	ENST00000256474.3
VHL	NM_198156.3	c.363C>A	p.Cys121Ter	stop_gained	2/2
VHL	NM_001354723.2	c.*40C>A		3_prime_UTR_variant	3/3
VHL	NR_176335.1	n.815C>A		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.486C>A	p.Cys162Ter	stop_gained	3/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Feb 26, 2016

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 25, 2019

This variant has been observed in individual(s) with von Hippel-Lindau syndrome (PMID: 28388566). ClinVar contains an entry for this variant (Variation ID: 223226). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the VHL gene (p.Cys162*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 52 amino acids of the VHL protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the VHL protein. Other variant(s) that disrupt this region (p.Ser183*) have been determined to be pathogenic (PMID: 8707293, 10567493, 11309459). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 03, 2023

The p.C162* pathogenic mutation (also known as c.486C>A), located in coding exon 3 of the VHL gene, results from a C to A substitution at nucleotide position 486. This changes the amino acid from a cysteine to a stop codon within coding exon 3. This alteration occurs at the 3' terminus of theVHL gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 23.9% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with VHL-related disease (Fagundes GFC et al. J Endocr Soc, 2019 Sep;3:1682-1692; Peng S et al. Oncotarget, 2017 Jun;8:38456-38465). Based on the supporting evidence, 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	0.49
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.76	D
MutationTaster	Benign	1.0	D;D
Vest4		0.84
GERP RS		3.1
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: rs5030622; hg19: chr3-10191493; COSMIC: COSV56542433;