3-10146561-G-C

Variant summary

Our verdict is Pathogenic. Variant got 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. V130F) 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

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.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 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-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 496061.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, Uncertain_significance=1}.
• 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 id is 2229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10146561-G-C is described in Lovd as [Pathogenic]. Variant chr3-10146561-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.388G>C	p.Val130Leu	missense_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3226G>C		intron_variant
VHL	NM_198156.3	c.341-3226G>C		intron_variant
VHL	NR_176335.1	n.717G>C		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.388G>C	p.Val130Leu	missense_variant	2/3	1	NM_000551.4	P1

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

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;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -

Chuvash polycythemia Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2003

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

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. 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

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 21, 2018

The p.V130L pathogenic mutation (also known as c.388G>C) is located in exon 2 of the VHL gene. This alteration 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 alteration has been reported in multiple unrelated patients and families meeting diagnostic criteria for 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). It has also been seen in the compound heterozygous state in one individual with polycythemia (Pastore YD et al. Blood. 2003 Feb;101(4):1591-5). 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	0.53	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
MutationTaster	Benign	1.0	A;A
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

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