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-T
• chr3-10142120-C-G

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: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, G2P
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000551.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.273C>A	p.Phe91Leu	missense	Exon 1 of 3	NP_000542.1	A0A024R2F2
	VHL	NM_001354723.2		c.273C>A	p.Phe91Leu	missense	Exon 1 of 3	NP_001341652.1	A0A8Q3WL21
	VHL	NM_198156.3		c.273C>A	p.Phe91Leu	missense	Exon 1 of 2	NP_937799.1	A0A0S2Z4K1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.273C>A	p.Phe91Leu	missense	Exon 1 of 3	ENSP00000256474.3	P40337-1
	VHL	ENST00000345392.3	TSL:1	c.273C>A	p.Phe91Leu	missense	Exon 1 of 2	ENSP00000344757.2	P40337-2
	VHL	ENST00000477538.2	TSL:1	n.319C>A		non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	Von Hippel-Lindau syndrome (1)
-	1	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.7
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-4.4	D
REVEL	Pathogenic	0.77
Sift	Uncertain	0.015	D
Sift4G	Benign	0.080	T
Polyphen		1.0	D
Vest4		0.61
MutPred		0.80		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;