3-10146561-G-C

Variant names:

• chr3-10146561-G-C
• rs104893830
• NM_000551.4:c.388G>C

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.388G>C​(p.Val130Leu) variant causes a missense change involving the alteration of a 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V130I) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.67
• Publications: 43 publications found

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 Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 20 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr3-10146561-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1735887.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant 3-10146561-G-C is Pathogenic according to our data. Variant chr3-10146561-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 2229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.388G>C	p.Val130Leu	missense	Exon 2 of 3	NP_000542.1
	VHL	NR_176335.1		n.717G>C		non_coding_transcript_exon	Exon 3 of 4
	VHL	NM_001354723.2		c.*18-3226G>C		intron	N/A	NP_001341652.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.388G>C	p.Val130Leu	missense	Exon 2 of 3	ENSP00000256474.3
	VHL	ENST00000477538.2	TSL:1	n.1268G>C		non_coding_transcript_exon	Exon 2 of 3
	VHL	ENST00000345392.3	TSL:1	c.341-3226G>C		intron	N/A	ENSP00000344757.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:2

Feb 26, 2016

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Aug 18, 2011

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing;curation

Chuvash polycythemia Pathogenic:1

Aug 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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

May 09, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 130 of the VHL protein (p.Val130Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with erythrocytosis and/or von Hippel-Lindau syndrome (PMID: 9829912, 10570625, 12202531, 12393546, 24581539). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 2229). 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 with a positive predictive value of 95%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on VHL function (PMID: 14556007). This variant disrupts the p.Val130 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 12624160, 20518900, 22393103), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 14, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V130L pathogenic mutation (also known as c.388G>C), located in coding exon 2 of the VHL gene, results from a G to C substitution at nucleotide position 388. The valine at codon 130 is replaced by leucine, an amino acid with highly similar properties. This variant was reported in individual(s) with features consistent with von Hippel-Lindau (VHL) syndrome (Zbar B et al. Hum Mutat. 1996;8(4):348-57; Dollfus H et al. Invest. Ophthalmol. Vis. Sci. 2002 Sep;43(9):3067-74; Gallou C et al. Hum. Mutat. 2004 Sep;24(3):215-24; Wang X et al. Urology. 2014 Mar;83(3):675.e1-5; Ambry internal data). This variant has also been detected in the compound heterozygous state in one individual with polycythemia (Pastore YD et al. Blood. 2003 Feb;101(4):1591-5). 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 variant is interpreted as a disease-causing mutation.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.92
Sift4G	Uncertain	0.012	D
Polyphen		0.98	D
Vest4		0.74
MutPred		0.89		Loss of sheet (P = 0.0457)
MVP		1.0
MPC		0.78
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.89
gMVP		0.93
Mutation Taster		=18/82	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs104893830; hg19: chr3-10188245; COSMIC: COSV56544519;