3-10146526-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.353T>C(p.Leu118Pro) 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. L118R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• 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 hotspot region, there are 14 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 chr3-10146526-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 428802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 3-10146526-T-C is Pathogenic according to our data. Variant chr3-10146526-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 428807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-10146526-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.353T>C	p.Leu118Pro	missense_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3261T>C		intron_variant
VHL	NM_198156.3	c.341-3261T>C		intron_variant
VHL	NR_176335.1	n.682T>C		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.353T>C	p.Leu118Pro	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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2022

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 118 of the VHL protein (p.Leu118Pro). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects VHL function (PMID: 14973063). 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: 428807). This variant is also known as c.566T>C (p.Leu189Pro). This missense change has been observed in individuals with von Hippel-Lindau (VHL) syndrome and clinical features of VHL (PMID: 7987306, 8956040, 9829912, 12202531, 17024664, 22799452, 25952756, 27527340). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2018

The p.L118P pathogenic mutation (also known as c.353T>C), located in coding exon 2 of the VHL gene, results from a T to C substitution at nucleotide position 353. The leucine at codon 118 is replaced by proline, an amino acid with very few similar properties. This pathogenic mutation has been reported in numerous individuals diagnosed with VHL (Crossey PA et al. Hum Mol Genet. 1994 Aug;3(8):1303-8; Zbar B et al. Hum Mutat. 1996;8(4):348-57; Olschwang S et al. Hum. Mutat. 1998;12:424-30; Yoshida M et al. Jpn J Cancer Res. 2000 Feb;91(2):204-12; Gallou C et al. Hum Mutat. 2004 Sep;24(3):215-24; Benhammou JN et al. J. Urol. 2010 Nov;184:1855-9; Dandanell M et al. BMC Med Genet. 2012 Jul 16;13:54; Wong M et al. Chin J Cancer. 2016 Aug;35:79). Authors of another study concurred that missense mutations in the VHL gene are associated with a higher risk of pheochromocytomas, however they divided missense mutations into two subgroups:surface missense amino acid substitution mutations (SM) and deep missense mutations (DM). Missense mutations in the SM group were found to be at a significantly higher risk for pheochromocytomas than missense mutations in the DM group. The p.L118P variant was categorized as a DM due to its location in the protein core and the disruption of protein function (Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9). Of note, this pathogenic mutation is also referred to as 566T>C in some literature. 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	0.99
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-4.7	D
REVEL	Pathogenic	0.95
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.93		Loss of sheet (P = 0.0043);
MVP		0.99
MPC		1.4
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs5030830; hg19: chr3-10188210; COSMIC: COSV56544274;