3-10142041-C-G

Position:

• chr3-10142041-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4 PS3_Supporting PM6 PP3 PM2_Supporting PM1

This summary comes from the ClinGen Evidence Repository: The NM_000551.4(VHL):c.194C>G (p.Ser65Trp) variant in VHL is a missense variant predicted to cause substitution of Ser by Trp at amino acid 65 (p.Ser65Trp).The CIViC database (https://civicdb.org) describes 17 unrelated individuals with clinically diagnosed VHL or cancers in VHL cancer spectrum, many with evidence of VHL in family history. The following PMIDs were used for proband counting (2 unrelated probands or families where noted, all others 1) 28650583(2pt), 17024664, 17392848, 28388566(2pt), 29294023(2pt), 22156657, 23407287, 9829911, 7728151, 18446368, 22357542, 11148816, 21463266, 20518900. In addition, 3 participating laboratories contributed a total of 5 unique subjects. Each subject was evaluated for meeting Danish, Consistent or Nonspecific and a total of 13.5 points was awarded, which constitutes strong evidence. (PS4_Met). A denovo case, 33yo Chinese man presented with Renal Cell Carcinoma, and had a history of urological surgery at the age of 23 years due to an epididymal cyst and an ophthalmologic surgery at 26 years of age for retinal detachment resulting from bilateral retinal angiomatosis. 7 relatives (parents and siblings) were tested for S65W, and it was not identified. The authors do not note confirming maternity/paternity. PMID:26622630 (PM6_Met). There is one variant present in gnomAD v4.1.0. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is not calculated. PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD, or if no GroupMax Filtering Allele Frequency is calculated (due to a single variant present) (PM2_Supporting). S65W significantly decreases the VHL protein binding to HIF-1alpha, preventing ubiquitination PMID:15611064 (PS3_Supporting). This variant resides within the VHL beta domain, a key functional domain. It is also defined as a mutational hotspot in Chinese populations (PMID:31620170) (PM1_Met). The computational predictor REVEL gives a score of 0.943, which is above the threshold of >0.664, evidence that correlates with impact to VHL function (PP3_Met). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel-Lindau disease (VHL disease) based on the ACMG/AMP criteria applied, as specified by the ClinGen VHL VCEP Version 1.0 (Specifications approval date: 02/26/2024. Variant Approval Date 06/25/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA020099/MONDO:0008667/078

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 4.92

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 11 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.194C>G	p.Ser65Trp	missense_variant	1/3	ENST00000256474.3
VHL	NM_001354723.2	c.194C>G	p.Ser65Trp	missense_variant	1/3
VHL	NM_198156.3	c.194C>G	p.Ser65Trp	missense_variant	1/2
VHL	NR_176335.1	n.264C>G		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.194C>G	p.Ser65Trp	missense_variant	1/3	1	NM_000551.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1450498 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721074

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 26, 2023	Published functional studies demonstrate a damaging effect: decreased VHL protein binding to HIF-1alpha, preventing ubiquitination (Miller 2005); Observed in multiple individuals with history consistent with pathogenic variants in this gene referred for genetic testing at GeneDx and in published literature (Stolle 1998, Hes 2007, Dandanell 2012); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17661816, 20233476, 27527340, 26622630, 30731206, 23384228, 18544564, 15611064, 9829911, 19602254, 22799452, 10567493, 24444636, 8730290, 25563310, 7987306, 15881703, 31176917, 30522901, 31620170) -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Von Hippel-Lindau syndrome Pathogenic:3

Pathogenic, no assertion criteria provided	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 30, 2008	- -
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	Myriad Genetics, Inc.	Feb 22, 2024	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 35505422, 15611064]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 35505422, 18446368, 28650583, 34566400, 35466127]. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Dec 17, 2023

This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 65 of the VHL protein (p.Ser65Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Von Hippel-Lindau (VHL) syndrome (PMID: 7728151, 7987306, 8730290, 9829911, 10567493, 17024664, 22799452, 23384228). This variant is also known as Ser136Trp. ClinVar contains an entry for this variant (Variation ID: 43597). 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 have shown that this missense change affects VHL function (PMID: 11331613, 15611064, 16669786, 18544564, 19602254). This variant disrupts the p.Ser65 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10567493, 12114495, 15611064, 22799452, 25282218). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Oct 07, 2021

The p.S65W pathogenic mutation (also known as c.194C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 194. The serine at codon 65 is replaced by tryptophan, an amino acid with highly dissimilar properties This alteration has been reported as a germline mutation in many families affected with von Hippel-Lindau (VHL) syndrome that had no history of pheochromocytomas (Zbar et al. Hum Mutat. 1996;8(4):348-57; Crossey et al. Hum Mol Genet. 1994 Aug;3(8):1303-8; Ong et al. Hum Mutat. 2007 Feb;28(2):143-9; Zhang et al. J Cancer Res Clin Oncol. 2008 Nov;134(11):1211-8; Zhou et al. Pathol Int. 2010 Jun;60(6):452-8; Hes FJ et al. Clin. Genet., 2007 Aug;72:122-9). It has also been reported as a de novo alteration in a Chinese individual diagnosed with bilateral renal cell carcinoma at the age of 33 (Zhang L et al. Oncol Lett, 2015 Aug;10:1087-1090). Functional studies have indicated that the p.S65W mutation leads to severely compromised tight junctions and an unstable protein, therefore classifying it as a Type 1 VHL mutation (Bangiyeva et al. BMC Cancer. 2009 Jul 14;9:229). Note that this alteration is also referred to as c.407C>G in some published literature. Based on the available evidence, p.S65W is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.6	D;D
REVEL	Pathogenic	0.94
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.93
MutPred		0.81		Gain of catalytic residue at L63 (P = 0.007);Gain of catalytic residue at L63 (P = 0.007);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.94
gMVP		1.0

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: rs5030826; hg19: chr3-10183725; COSMIC: COSV56543220; COSMIC: COSV56543220;