chr3-10142104-C-T

Variant names:

• chr3-10142104-C-T
• rs730882034
• NM_000551.4:c.257C>T

Variant summary

Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_Supporting PS4 PP1_Strong

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.4(VHL):c.257C>T (p.Pro86Leu) is a missense variant predicted to cause substitution of Proline by Leucine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This is identified in over 10 probands meeting either Danish criteria for VHL, or harboring other consistent features with VHL. The total phenotype points is 7.5, which meets the VHL VCEP specification of PS4 (5-15 phenotype points) (PMIDs:7728151; 27527340; 29437867; 21463266). The variant has been reported to segregate with von Hippel Lindau syndrome in at least 7 affected family members from 2 families (PP1_Strong; PMID:7728151). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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/CA020186/MONDO:0008667/078

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 4.84

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 9 ACMG points.

• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP1: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VHL	NM_000551.4	c.257C>T	p.Pro86Leu	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.257C>T	p.Pro86Leu	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.257C>T	p.Pro86Leu	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.327C>T		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VHL	ENST00000256474.3	c.257C>T	p.Pro86Leu	missense_variant	Exon 1 of 3	1	NM_000551.4	ENSP00000256474.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:4

Feb 02, 2016

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: c.257C>T affects a conserved nucleotide, resulting in amino acid change from Pro to Leu. 4/4 in-silico tools predict this variant to be damaging. This variant was not found in 102226 control chromosomes. This variant has been reported in multiple VHL pts with clear co-segregation of the variant with disease in the families. Variants P86A, P86R, and P86S are all listed as disease mutation in HGMD and have been reported in multiple publications, suggesting the codon 86 is a hypermutable amino acid and a hotspot for mutations. In addition, one clinical laboratory (via Clinvar) classified this variant as pathogenic. Taken together, this variant was classified as a Pathogenic. -

Aug 24, 2020

Clinical Genomics Labs, University Health Network

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 26, 2016

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 25, 2024

ClinGen VHL Variant Curation Expert Panel, ClinGen

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The variant NM_000551.4(VHL):c.257C>T (p.Pro86Leu) is a missense variant predicted to cause substitution of Proline by Leucine. This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This is identified in over 10 probands meeting either Danish criteria for VHL, or harboring other consistent features with VHL. The total phenotype points is 7.5, which meets the VHL VCEP specification of PS4 (5-15 phenotype points) (PMIDs:7728151; 27527340; 29437867; 21463266). The variant has been reported to segregate with von Hippel Lindau syndrome in at least 7 affected family members from 2 families (PP1_Strong; PMID: 7728151). In summary, this variant meets the criteria to be classified as Pathogenic for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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). -

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

May 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 86 of the VHL protein (p.Pro86Leu). 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, 27527340; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.470C>T, p.Pro157Leu. ClinVar contains an entry for this variant (Variation ID: 182977). 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%. This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8634692, 9829912, 19464396, 27057652, 27527340). 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

Oct 07, 2021

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P86L pathogenic mutation (also known as c.257C>T), located in coding exon 1 of the VHL gene, results from a C to T substitution at nucleotide position 257. The proline at codon 86 is replaced by leucine, an amino acid with very few similar properties. This pathogenic mutation has been found in multiple individuals meeting clinical criteria for Von Hippel-Lindau syndrome with symptoms including retinal angiomas, CNS hemangioblastomas, renal cell carcinoma, and pancreatic cysts/tumors (Chen F et al. Hum. Mutat. 1995; 5(1):66-75; Kondo et al. Hum. Mol. Genet. 1995 Dec;4(12):2233-7; Yoshida M et al. Jpn. J. Cancer Res. 2000 Feb; 91(2):204-12; Ong KR et al. Hum. Mutat. 2007 Feb;28(2):143-9; Zhang J et al J. Cancer Res. Clin. Oncol. 2008 Nov;134(11):1211-8; Wong M et al. Chin J Cancer. 2016 Aug;35:79). Three unique alterations located at the same position, p.P86A, p.P86S, and p.P86R, have each been documented in the literature as having an association with Von Hippel-Lindau syndrome suggesting this codon may represent a mutation hotspot. Of note, the p.P86L (c.257C>T) alteration has also been reported as p.P157L (c.470C>T) in some literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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	0.91
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.4	L;L
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0020	.;D
Sift4G	Benign	0.27	T;D
Polyphen		1.0	D;D
Vest4		0.87
MutPred		0.93		Gain of catalytic residue at P86 (P = 0.0143);Gain of catalytic residue at P86 (P = 0.0143);
MVP		1.0
MPC		1.1
ClinPred		0.99	D
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.91
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: rs730882034; hg19: chr3-10183788; COSMIC: COSV56546214; COSMIC: COSV56546214;