3-10141875-G-T

Position:

• chr3-10141875-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1

The NM_000551.4(VHL):​c.28G>T​(p.Glu10*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000506 in 1,382,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000051 (0 hom.)
• Consequence: VHL NM_000551.4 stop_gained
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.00800

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 106 pathogenic variants in the truncated region.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.28G>T	p.Glu10*	stop_gained	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.28G>T	p.Glu10*	stop_gained	1/3		NP_001341652.1
VHL	NM_198156.3	c.28G>T	p.Glu10*	stop_gained	1/2		NP_937799.1
VHL	NR_176335.1	n.98G>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.28G>T	p.Glu10*	stop_gained	1/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000506 AC: 7 AN: 1382114 Hom.: 0 Cov.: 32 AF XY: 0.00000441 AC XY: 3 AN XY: 679680

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000654

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This variant changes 1 nucleotide in exon 1 of the VHL gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. However, there is a naturally occurring VHL protein isoform that has start of translation at methionine 54 and appears to retain tumor suppressor activity (PMID: 9671762, 9751722, 10102622), which may ameliorate the deleterious effects of this N-terminal frameshift. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with congenital erythrocytosis (PMID: 24115288). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of VHL function is a known mechanism of disease (clinicalgenome.org). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 10, 2017	- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 03, 2023

This sequence change creates a premature translational stop signal (p.Glu10*) in the VHL gene. It is unclear whether it will result in an absent or disrupted protein product because an in-frame methionine located at codon 54 has the potential to rescue this variant. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital erythrocytosis (PMID: 24115288). ClinVar contains an entry for this variant (Variation ID: 548745). Several studies have shown that the VHL protein created from a downstream methionine located at codon 54 is biologically active, and exhibits properties similar to the full-length, wild-type protein (PMID: 9671762, 9751722). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 10, 2023

The p.E10* variant (also known as c.28G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 28. This changes the amino acid from a glutamic acid to a stop codon within coding exon 1. This alteration was identified as heterozygous in a patient from France with congenital erythrocytosis (Bento C et al. Hum Mutat, 2014 Jan;35:15-26). Premature stop codons are typically deleterious in nature; however, an alternate initiation codon exists 44 residues downstream from this alteration and is reported to result in a biologically active isoform known as VHL19 (Schoenfeld A et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Jul; 95(15):8817-22; Iliopoulos O et al. Proc. Natl. Acad. Sci. U.S.A. 1998 Sep; 95(20):11661-6). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.29
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.49	N
Vest4		0.50
GERP RS		2.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1

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: rs1057519261; hg19: chr3-10183559;