rs1060503563

Variant names:

• chr3-10142120-C-A
• rs1060503563
• NM_000551.4:c.273C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-10142120-C-A
• chr3-10142120-C-G
• chr3-10142120-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PS3_Supporting PP3 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The NM_000551.3(VHL):c.273C>A (p.Phe91Leu) variant in VHL is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 91. This variant has been reported in 2 unrelated probands. Dolfus et al reports a VHL subject with (c.263 G>C; p.F91L) from a family in the French VHL Registry, the individual did not have renal involvement. No further phenotypic description is provided. (PMID:15300849). Gallou et al (PMID:15300849) reports a VHL subject with retinal hemangioblastomas and (c.273 C>G and p.F91L). Olschwang et al (1998) is likely the same subject as Gallou et al and is not included in the proband count. Two of three participating commercial laboratories reports 4 cases with this variant, however none have VHL-related cancers. Given the sparse phenotypic descriptions in the two publications, and the 4 samples lacking VHL phenotypes from commercial laboratories, the ClinGen VHL VCEP does not recommend applying this code. (PS4_NOT_MET). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In Tarade et al, an in vitro pVHL-HIFa binding assay followed by immunoblotting showed the the F91L variant abolished all binding to HIF1a and HIF2a (PMID:31337753)(PS3_Supporting).This variant resides within a region of VHL that is defined as a critical functional domain (the Beta Domain) (PM1). The computational predictor REVEL gives a score of 0.773, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Uncertain 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/CA16611270/MONDO:0008667/078

• Frequency: Genomes: not found (cov: 33)
• Consequence: VHL NM_000551.4 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 1.67
• Publications: 6 publications found

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]

VHL Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• von Hippel-Lindau disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• renal cell carcinoma

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• autosomal recessive secondary polycythemia not associated with VHL gene

  Inheritance: AR Classification: STRONG Submitted by: Ambry Genetics
• Chuvash polycythemia

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PM1: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PP3: 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.273C>A	p.Phe91Leu	missense_variant	Exon 1 of 3	ENST00000256474.3	NP_000542.1
VHL	NM_001354723.2	c.273C>A	p.Phe91Leu	missense_variant	Exon 1 of 3		NP_001341652.1
VHL	NM_198156.3	c.273C>A	p.Phe91Leu	missense_variant	Exon 1 of 2		NP_937799.1
VHL	NR_176335.1	n.343C>A		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.273C>A	p.Phe91Leu	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: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

Von Hippel-Lindau syndrome Uncertain:1

Jun 25, 2024

ClinGen VHL Variant Curation Expert Panel, ClinGen

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The NM_000551.3(VHL):c.273C>A (p.Phe91Leu) variant in VHL is a missense variant predicted to cause substitution of phenylalanine by leucine at amino acid 91. This variant has been reported in 2 unrelated probands. Dolfus et al reports a VHL subject with (c.263 G>C; p.F91L) from a family in the French VHL Registry, the individual did not have renal involvement. No further phenotypic description is provided. (PMID: 15300849). Gallou et al (PMID:15300849) reports a VHL subject with retinal hemangioblastomas and (c.273 C>G and p.F91L). Olschwang et al (1998) is likely the same subject as Gallou et al and is not included in the proband count. Two of three participating commercial laboratories reports 4 cases with this variant, however none have VHL-related cancers. Given the sparse phenotypic descriptions in the two publications, and the 4 samples lacking VHL phenotypes from commercial laboratories, the ClinGen VHL VCEP does not recommend applying this code. (PS4_NOT_MET). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). In Tarade et al, an in vitro pVHL-HIFa binding assay followed by immunoblotting showed the the F91L variant abolished all binding to HIF1a and HIF2a (PMID: 31337753)(PS3_Supporting). This variant resides within a region of VHL that is defined as a critical functional domain (the Beta Domain) (PM1). The computational predictor REVEL gives a score of 0.773, which is above the threshold of >=0.664, evidence that correlates with impact to VHL function (PP3). In summary, this variant meets the criteria to be classified as Uncertain 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). -

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

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 91 of the VHL protein (p.Phe91Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinal hemangioblastoma (PMID: 12202531). ClinVar contains an entry for this variant (Variation ID: 411978). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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: 31337753). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F91L variant (also known as c.273C>A), located in coding exon 1 of the VHL gene, results from a C to A substitution at nucleotide position 273. The phenylalanine at codon 91 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in one individual with a retinal hemangioblastoma (Dollfus H et al. Invest. Ophthalmol. Vis. Sci., 2002 Sep;43:3067-74), and an alteration with the same amino acid change, but different nucleotide substitution (c.273C>G; F91L) has been reported in one family reported to have with VHL, but no additional clinical details provided (Gallou C et al. Hum. Mutat., 2004 Sep;24:215-24). In vitro studies indicate this alteration disrupts binding to both HIF1α and HIF2α (Tarade D et al. Nat Commun., 2019 07;10:3293). Based on our internal structural assessment, this alteration results in perturbation of the HIF1α-binding pocket (Ambry internal data). However, this alteration has been observed in our cohort in individuals who do not have a personal or family history that is consistent with VHL-associated disease (Ambry internal data). 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 available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.78	T;T
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M;M
PhyloP100		1.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.015	.;D
Sift4G	Benign	0.080	T;D
Polyphen		1.0	D;D
Vest4		0.61
MutPred		0.80		Gain of disorder (P = 0.1198);Gain of disorder (P = 0.1198);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		2.3
PromoterAI		0.070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.94
gMVP		0.95
Mutation Taster		=15/85	disease causing

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

Other links and lift over

dbSNP: rs1060503563; hg19: chr3-10183804;