chr3-10146528-T-C

Variant names:

• chr3-10146528-T-C
• rs1553619948
• NM_000551.4:c.355T>C

Variant summary

Our verdict is Pathogenic. The variant received 24 ACMG points: 24P and 0B. PS1_Very_Strong PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_000551.4(VHL):​c.355T>C​(p.Phe119Leu) variant causes a missense 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 (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F119C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.18
• Publications: 2 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 24 ACMG points.

• PS1: Transcript NM_000551.4 (VHL) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM1: In a hotspot region, there are 35 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 19 uncertain in NM_000551.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 3-10146528-T-C is Pathogenic according to our data. Variant chr3-10146528-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 496059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.355T>C	p.Phe119Leu	missense_variant	Exon 2 of 3	ENST00000256474.3	NP_000542.1
VHL	NR_176335.1	n.684T>C		non_coding_transcript_exon_variant	Exon 3 of 4
VHL	NM_001354723.2	c.*18-3259T>C		intron_variant	Intron 2 of 2		NP_001341652.1
VHL	NM_198156.3	c.341-3259T>C		intron_variant	Intron 1 of 1		NP_937799.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.355T>C	p.Phe119Leu	missense_variant	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 05, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The c.355T>C (F119L) in VHL is a missense variant involving a highly conserved nucleotide and 3/4 in silico tools predict this variant to be deleterious (no prediction for SIFT). The variant was not found in the general population but was reported in at least 3 VHL patients. Another variant, c.357C>G, leading to the same amino acid change (F119L) and c.356T>C (F119S) have been reported in multiple VHL pts, indicating that this codon is a mutation hotspot. Additionally this variant has been identified as a somatic mutation in multiple renal cell carcinomas. Taken together, this is a disease variant and was classified as Pathogenic. -

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

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is also known as P190L. ClinVar contains an entry for this variant (Variation ID: 496059). 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 have shown that this missense change affects VHL function (PMID: 21715564, 23840444). For these reasons, this variant has been classified as Pathogenic. This missense change has been observed in individuals with VHL-related conditions (PMID: 7728151, 12000816, 16142346, 19270817). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 119 of the VHL protein (p.Phe119Leu). This variant is not present in population databases (gnomAD no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jan 29, 2020

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F119L pathogenic mutation (also known as c.355T>C), located in coding exon 2 of the VHL gene, results from a T to C substitution at nucleotide position 355. The phenylalanine at codon 119 is replaced by leucine, an amino acid with highly similar properties. In one study, in silico, in vitro, and bacterial assays showed that the p.F119L alteration results in loss of folding, stability, and function of the VHL protein (Shmueli MD et al. PLoS ONE. 2013 Jun;8:e66333). This mutation has been identified in multiple individuals/families with a clinical diagnosis or suspicion of von-Hippel-Lindau (VHL) syndrome (Cho HJ et al. J. Korean Med. Sci., 2009 Feb;24:77-83; Klein B et al. Hum. Genet., 2001 May;108:376-84; Ambry internal data). It has also been reported in a patient with non-syndromic pheochromocytoma (Neumann HP et al. N. Engl. J. Med. 2002 May; 346:1459-66), a patient with bilateral pheochromocytomas (Albattal S et al. Oncotarget, 2019 Oct;10:5919-5931), and a patient with bilateral adrenal pheochromocytoma and a carotid paraganglioma (Boedeker CC et al. J. Clin. Endocrinol. Metab. 2009 Jun; 94:1938-44). In one functional study, this alteration's interactions with hypoxia-inducible factors (HIF), which affect protein stability, were similar to at least one alteration classified as VLP at Ambry (W88C) (Rechsteiner MP et al. Cancer Res. 2011 Aug; 71(16):5500-11; Ambry internal data). Of note, this alteration is also designated as 568C>G in published literature. 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	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.81	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.93
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.93		Loss of sheet (P = 0.0228);
MVP		1.0
MPC		1.2
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.94
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1553619948; hg19: chr3-10188212; COSMIC: COSV56547209;