rs1553619948

Positions:

• chr3-10146528-T-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.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 variant affecting the same amino acid position, but resulting in a different missense (i.e. F119S) 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:3
• Conservation: PhyloP100: 6.18

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 strand (size 5) in uniprot entity VHL_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• 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 id is 496059.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.355T>C	p.Phe119Leu	missense_variant	2/3	1	NM_000551.4	ENSP00000256474	P1

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

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 05, 2016

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This missense change has been observed in individuals with VHL-related conditions (PMID: 7728151, 12000816, 16142346, 19270817). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 21715564, 23840444). 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. ClinVar contains an entry for this variant (Variation ID: 496059). This variant is also known as P190L. This variant is not present in population databases (gnomAD no frequency). 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). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 29, 2020

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
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1553619948; hg19: chr3-10188212; COSMIC: COSV56547209;