3-10146603-G-T

Variant names:

• chr3-10146603-G-T
• rs869025650
• NM_000551.4:c.430G>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.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]

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 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_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10146603-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.430G>T	p.Gly144*	stop_gained	Exon 2 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.*18-3184G>T		intron_variant	Intron 2 of 2		NP_001341652.1
VHL	NM_198156.3	c.341-3184G>T		intron_variant	Intron 1 of 1		NP_937799.1
VHL	NR_176335.1	n.759G>T		non_coding_transcript_exon_variant	Exon 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.430G>T	p.Gly144*	stop_gained	Exon 2 of 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

Feb 26, 2016

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

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Apr 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Gly144*) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 70 amino acid(s) of the VHL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pheochromocytoma (PMID: 9829911). This variant is also known as 643G>T. ClinVar contains an entry for this variant (Variation ID: 223208). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the VHL protein in which other variant(s) (p.Arg161*) have been determined to be pathogenic (PMID: 14722919, 18446368, 19602254, 24206762, 24301059). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 11, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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;