3-10149848-C-G

Position:

• chr3-10149848-C-G

Variant summary

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

The ENST00000256474.3(VHL):​c.525C>G​(p.Tyr175*) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. Y175Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL ENST00000256474.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.797

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 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 50 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10149848-C-G is Pathogenic according to our data. Variant chr3-10149848-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 182974.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.525C>G	p.Tyr175*	stop_gained	3/3	ENST00000256474.3	NP_000542.1
VHL	NM_198156.3	c.402C>G	p.Tyr134*	stop_gained	2/2		NP_937799.1
VHL	NM_001354723.2	c.*79C>G		3_prime_UTR_variant	3/3		NP_001341652.1
VHL	NR_176335.1	n.854C>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.525C>G	p.Tyr175*	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 04, 2016

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 03, 2020

This sequence change results in a premature translational stop signal in the VHL gene (p.Tyr175*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acids of the VHL protein. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the elongin C binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 9447969, 10900011). Other variants that disrupt this region (p.Tyr185*) have been determined to be pathogenic (PMID: 23298237, 7987306). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individuals with von Hippel-Lindau (VHL) syndrome (PMID: 9829912, 12202531, 15300849, 27527340). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 182974). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.72	D
MutationTaster	Benign	1.0	D;D
Vest4		0.95
GERP RS		1.9
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: rs5030835; hg19: chr3-10191532; COSMIC: COSV56543727;