rs869025637

Variant names:

• chr3-10146512-A-G
• rs869025637
• NM_000551.4:c.341-2A>G

Your query was ambiguous. Multiple possible variants found:

• chr3-10146512-A-G
• chr3-10146512-A-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The variant NM_000551.3(VHL):c.341-2A>G is a canonical splice site within the 1st intron of the VHL gene, and is predicted to undergo nonsense mediated decay (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been reported in at least 3 studies, in cases or families with VHL syndrome or VHL-related cancers. PMIDs: 17661816, 17024664, 27539324, CIViC EIDs (https://civicdb.org): 5748, 5730. Two commercial laboratories report 1 case each, both with a history of VHL-related cancers. One had an additional clinical diagnosis of VHL and a first degree relative with multiple VHL-related cancers in age 30-40yrs who was also VHL positive (PS4_Moderate). Although PP3 was not applied due to use of PVS1, we include the note that multiple splice predictors were used to evaluate the splice site. VarSeak supports the impact of disrupting this canonical splice site (Class 5) and the Splice AI score is 0.93, indicating impact on splicing. In summary, this variant meets the criteria to be classified as Pathogenic 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/CA357004/MONDO:0008667/078

• Frequency: Genomes: not found (cov: 32)
• Consequence: VHL NM_000551.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.17
• Publications: 3 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.341-2A>G		splice_acceptor intron	N/A	NP_000542.1
	VHL	NM_001354723.2		c.*18-3275A>G		intron	N/A	NP_001341652.1
	VHL	NM_198156.3		c.341-3275A>G		intron	N/A	NP_937799.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.341-2A>G		splice_acceptor intron	N/A	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.341-3275A>G		intron	N/A	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.1221-2A>G		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
3	-	-	Von Hippel-Lindau syndrome (3)
1	-	-	Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Benign	-0.10
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		7.2
GERP RS		5.0
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.93		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869025637; hg19: chr3-10188196; COSMIC: COSV56544966;