rs869025655

chr3-10146625-T-Cchr3-10146625-T-G

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.452T>C(p.Ile151Thr) 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. I151S) 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 9 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 chr3-10146625-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 223215.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 3-10146625-T-C is Pathogenic according to our data. Variant chr3-10146625-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 428803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
VHL	NM_000551.4	c.452T>C	p.Ile151Thr	missense_variant	2/3	ENST00000256474.3
VHL	NM_001354723.2	c.*18-3162T>C		intron_variant
VHL	NM_198156.3	c.341-3162T>C		intron_variant
VHL	NR_176335.1	n.781T>C		non_coding_transcript_exon_variant	3/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
VHL	ENST00000256474.3	c.452T>C	p.Ile151Thr	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

Von Hippel-Lindau syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Feb 26, 2019

Variant summary: The variant, VHL c.452T>C (p.Ile151Thr, also known as c.655T>C, p.Ile222Thr) results in a non-conservative amino acid change located in the von Hippel-Lindau disease tumour suppressor, alpha domain and von Hippel-Lindau disease tumour suppressor, beta/alpha domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246370 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with Von Hippel-Lindau Syndrome (Hes_2007, Ong_2007, Sriphrapradang_2017, Krauss_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence assessing the variant effect on the downstream signaling mechanism of VHL but does not allow convincing conclusions about the variant effect (Walmsley_2006). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Neoplasm Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Dec 20, 2021

ACMG categories: PS1,PM2,PM7,PP3,PP4,PP5 -

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Feb 27, 2020

This variant has been reported in numerous individuals affected with von Hippel-Lindau (VHL) syndrome (PMID: 10567493, 28469506, 17661816, 17024664, 11309459). This variant is also known as 665T>C in the literature. ClinVar contains an entry for this variant (Variation ID: 428803). For these reasons, this variant has been classified as Pathogenic. Different missense substitutions at this codon (p.Ile151Ser and p.Ile151Phe) have been reported in several individuals affected with VHL syndrome (PMID: 22357542, 25078357). 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 variant is not present in population databases (ExAC no frequency). This sequence change replaces isoleucine with threonine at codon 151 of the VHL protein (p.Ile151Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 17, 2019

The p.I151T pathogenic mutation (also known as c.452T>C), located in coding exon 2 of the VHL gene, results from a T to C substitution at nucleotide position 452. The isoleucine at codon 151 is replaced by threonine, an amino acid with similar properties. The p.I151T alteration, also referred to as 665T>C in some literature, has been reported in individuals with a diagnosis or clinical features of VHL (Gläsker S et al. J. Neurol. Neurosurg. Psychiatr. 1999 Dec;67:758-62; Gläsker S et al. J. Neurol. Neurosurg. Psychiatry. 2001 May;70:644-8; Hes FJ et al. Clin. Genet. 2007 Aug;72:122-9; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122; Krauss T et al. Endocr. Relat. Cancer. 2018 09;25:783-793; Ambry internal data). Based on internal structural analysis, this variant is more disruptive than known pathogenic variants (Testa A et al. J. Am. Chem. Soc., 2018 07;140:9299-9313). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. As such, 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	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.97
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.87		Loss of sheet (P = 0.0043);
MVP		1.0
MPC		1.2
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.94
gMVP		0.98

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: rs869025655; hg19: chr3-10188309; COSMIC: COSV56548828;