3-10146603-G-T

Position:

• chr3-10146603-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000551.4(VHL):​c.430G>T​(p.Gly144*) variant causes a stop gained change. 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: 4.59

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 42 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-10146603-G-T is Pathogenic according to our data. Variant chr3-10146603-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 223208.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-10146603-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.430G>T	p.Gly144*	stop_gained	2/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.*18-3184G>T		intron_variant			NP_001341652.1
VHL	NM_198156.3	c.341-3184G>T		intron_variant			NP_937799.1
VHL	NR_176335.1	n.759G>T		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.430G>T	p.Gly144*	stop_gained	2/3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2020

For these reasons, this variant has been classified as Pathogenic. A different truncation (p.Arg161*) that lies downstream of this variant has been determined to be pathogenic (PMID: 19602254, 18446368, 24301059, 14722919, 24206762). Additionally, this truncation disrupts a significant portion of the VHL elongin binding domain (PMID: 14987375), which is required for protein stability and tumor suppressive activity (PMID: 10900011). Experimental studies have shown that missense substitutions in this domain (p.Arg161Gln, p.Cys162Trp, p.Arg167Gly, p.Arg167Trp, p.Arg167Gln) impair protein function in vitro (PMID: 25371412, 21715564, 17350623, 19602254, 15574766, 19030229, 19252526, 14973063), indicating that the amino acid residues disrupted by this truncating variant are important for protein function. This variant has been reported in a family affected with pheochromocytoma (PMID: 9829911). This variant is also known as 643G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 223208). 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.Gly144*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acids of the VHL protein. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2024

The p.G144* pathogenic mutation (also known as c.430G>T), located in coding exon 2 of the VHL gene, results from a G to T substitution at nucleotide position 430. This changes the amino acid from a glycine to a stop codon within coding exon 2. This alteration occurs at the 3' terminus of the VHL gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 33% 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 variant was reported in multiple individuals who met clinical criteria or have features consistent with von Hippel-Lindau syndrome (Stolle C et al. Hum Mutat, 1998;12:417-23; Hes FJ et al. Clin Genet, 2007 Aug;72:122-9; Mathó C et al. Genet Test Mol Biomarkers, 2016 Dec;20:771-776; Ambry internal data). This variant has also been reported in a de novo mutation in one individual who met clinical criteria of von Hippel-Lindau syndrome (Nordstrom-O'Brien M et al. Hum Mutat, 2010 May;31:521-37). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant 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	0.63
CADD	Pathogenic	41
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.95
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.41		Position offset: 33

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869025650; hg19: chr3-10188287; COSMIC: COSV56545017;