rs1553619431

Positions:

• chr3-10142109-T-A
• chr3-10142109-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.262T>A​(p.Trp88Arg) 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. W88C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 4.90

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 10 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 chr3-10142111-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant 3-10142109-T-A is Pathogenic according to our data. Variant chr3-10142109-T-A is described in ClinVar as [Pathogenic]. Clinvar id is 456577.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.262T>A	p.Trp88Arg	missense_variant	1/3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.262T>A	p.Trp88Arg	missense_variant	1/3		NP_001341652.1
VHL	NM_198156.3	c.262T>A	p.Trp88Arg	missense_variant	1/2		NP_937799.1
VHL	NR_176335.1	n.332T>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.262T>A	p.Trp88Arg	missense_variant	1/3	1	NM_000551.4	ENSP00000256474	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 01, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2016	Variant summary: This c.262T>A variant affects a conserved nucleotide, resulting in amino acid change from Trp to Arg in beta domain of VHL protein. 5/5 in-silico tools predict this variant to be damaging. This variant was not found in approximately 102226 control chromosomes including the large and broad populations from ExAC. This variant has been reported in at least ten independent VHL patients, two of whom carried the variant as somatic occurrence. In a family, the variant was found in two affected members, suggesting a possible cosegregation of the variant with disease (Glasker_2001). Another nucleotide change leading to the same amino acid change c.262T>C is a pathogenic variant, a strong evidence that this nucleotide change is also pathogenic. In addition, codon 88 is a mutational hot spot in which other potentially pathogenic variants such as .W88C, p.W88S, p.W88* (c.263G>A) and p.W88* (c.264G>A) have been reported in VHL disease or its related cancers. Taken together, this variant has been classified as a Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genomics Labs, University Health Network	Oct 16, 2019	- -

Chuvash polycythemia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 21, 2023

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 21, 2017

A different variant (c.262T>C) giving rise to the same protein effect observed here (p.Trp88Arg) has been reported in individuals affected with Von Hippel-Lindau syndrome (PMID: 12624160, 17688370, Invitae). In addition, a different missense substitution at this codon (p.Trp88Cys) has been determined to be likely pathogenic (PMID: 10567493, 21715564). This suggests that the tryptophan residue is critical for VHL protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces tryptophan with arginine at codon 88 of the VHL protein (p.Trp88Arg). The tryptophan residue is highly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Von Hippel-Lindau syndrome (PMID: 10567493, 7728151, 17024664, 8956040). -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 16, 2014

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2020

The p.W88R variant (also known as c.262T>A), located in coding exon 1 of the VHL gene, results from a T to A substitution at nucleotide position 262. The tryptophan at codon 88 is replaced by arginine, an amino acid with dissimilar properties. This alteration (also designated 475T>A) was detected in multiple patients who met clinical criteria or presented with clinical features of Von Hippel-Lindau (VHL) Syndrome (Chen F et al. Hum. Mutat., 1995;5:66-75; Gläsker S et al. J. Neurol. Neurosurg. Psychiatry, 1999 Dec;67:758-62; Jilg CA et al. Urol. Int., 2012 Dec;88:71-8; Ong KR et al. Hum. Mutat., 2007 Feb;28:143-9; Rocha JC et al. J. Med. Genet., 2003 Mar;40:e31; Stanojevic BR et al. Neoplasma, 2007;54:402-6; Zbar B et al. Hum. Mutat., 1996;8:348-57). In addition, a similar alteration resulting in the same amino acid change (W88R) but with a different nucleotide change (c.262T>C) has been reported in VHL patients (Hong B et al. Front Genet, 2019 Sep;10:867; Kim WT et al. J. Korean Med. Sci., 2009 Dec;24:1145-9). Based on internal structural analysis, W88R is at a putative HIF1 binding interface and the variant is moderately destabilizing to the local structure and more disruptive than known variants in the region (Shmueli MD et al. PLoS ONE, 2014 Oct;9:e109864; Van Molle I et al. Chem. Biol., 2012 Oct;19:1300-12). 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	0.53	D
BayesDel_noAF	Pathogenic	0.53
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	0.68	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	0.80	D;D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-12	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;D
Vest4		0.99
MutPred		0.92		Gain of disorder (P = 3e-04);Gain of disorder (P = 3e-04);
MVP		1.0
MPC		1.5
ClinPred		0.99	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.94
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553619431; hg19: chr3-10183793; COSMIC: COSV56542744; COSMIC: COSV56542744;