3-10142097-G-T

Position:

• chr3-10142097-G-T

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.250G>T​(p.Val84Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000689 in 1,451,712 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 Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 6.11

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 20 ACMG points.

• PS1: Transcript NM_000551.4 (VHL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a strand (size 5) in uniprot entity VHL_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 3-10142097-G-T is Pathogenic according to our data. Variant chr3-10142097-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 2236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10142097-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
VHL	NM_000551.4	c.250G>T	p.Val84Leu	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.250G>T	p.Val84Leu	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.250G>T	p.Val84Leu	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.320G>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.250G>T	p.Val84Leu	missense_variant	1/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451712 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 722542

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Feb 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 02, 2012	The Val84Leu variant has previously been reported in the literature in several i ndividuals with clinical features consistent with VHL syndrome. Six individuals with bilateral pheochromocytomas have been reported, four of whom had a family h istory (Abbott 2006, Crossey 1995, Klein 2001, Leonardi 2011). This variant segr egated with disease in two individuals from two families (Crossey 1995, Abbott 2 006) and is currently considered to be causative for VHL type 2C (Crossey 1995). In addition, this variant (caused by a different nucleotide change, 250G>C) was reported as a de novo variant in an individual with sporadic disease and was ab sent from 400 control chromosomes (Leonardi 2011). This variant is listed in dbS NP (rs5030827) as a clinically associated variant. In summary, this variant is h ighly likely to be pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2006	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 15, 2022

For these reasons, this variant has been classified as Pathogenic. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 11331612, 11331613, 12510195, 19228690, 19602254, 21791076). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. ClinVar contains an entry for this variant (Variation ID: 2236). This missense change has been observed in individual(s) with von Hipple Lindau type 2C (PMID: 8592333, 11409863, 16502427, 19215943, 19270817, 25078357). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 84 of the VHL protein (p.Val84Leu). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Feb 01, 2024

VHL: PS1, PM1, PM2, PM5, PP3 -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2022

The p.V84L pathogenic mutation (also known as c.250G>T), located in coding exon 1 of the VHL gene, results from a G to T substitution at nucleotide position 250. The valine at codon 84 is replaced by leucine, an amino acid with highly similar properties. This mutation has been reported in multiple families with early-onset and/or bilateral pheochromocytomas (Crossey PA et al. J Med Genet, 1995 Nov;32:885-6; Klein B et al. Hum Genet, 2001 May;108:376-84; Kang HC et al. Oncol Rep, 2005 Oct;14:879-83; Abbott MA et al. Am J Med Genet A, 2006 Apr;140:685-90). Structural analysis of this variant demonstrated impaired formation of stable pVHL-ElonginC-ElonginB (VCB) complexes in vitro and CBCVHL ubiquitin ligase complexes in vivo, and functional analyses indicated this variant is mildly defective in HIF-1α regulation, suggesting the possibility that a low level of HIF-1/2α dysregulation contributes to the pathogenesis of pheochromocytomas (Knauth K et al. J Biol Chem, 2009 Apr;284:10514-22). Another functional analysis showed low levels of HIF-2α similar to those observed with wild-type VHL but elevated levels of α5 integrin compared to wild-type VHL (Bangiyeva V et al. BMC Cancer, 2009 Jul;9:229). Another alteration at the same codon, p.V84M (c.250G>A), has been described in families with early-onset pheochromocytomas (Stanojevic BR et al. Neoplasma. 2007;54:402-6; Eisenhofer G et al. Horm. Metab. Res. 2012 May;44(5):343-8). Of note, this alteration is also designated as 463G>T in the literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;.
Eigen	Benign	-0.051
Eigen_PC	Benign	0.076
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.73	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.3	D
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-2.1	N;N
REVEL	Uncertain	0.63
Sift	Uncertain	0.0080	.;D
Sift4G	Uncertain	0.018	D;T
Polyphen		0.017	B;B
Vest4		0.68
MutPred		0.94		Loss of MoRF binding (P = 0.1081);Loss of MoRF binding (P = 0.1081);
MVP		1.0
MPC		0.56
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.91
gMVP		0.98

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: rs5030827; hg19: chr3-10183781;