rs869025637

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS4_ModeratePVS1PM2_Supporting

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
ENST00000256474.3 splice_acceptor

Scores

4
1
2
Splicing: ADA: 1.000
2

Clinical Significance

Pathogenic reviewed by expert panel P:4

Conservation

PhyloP100: 7.17
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
VHLNM_000551.4 linkuse as main transcriptc.341-2A>G splice_acceptor_variant ENST00000256474.3 NP_000542.1
VHLNM_001354723.2 linkuse as main transcriptc.*18-3275A>G intron_variant NP_001341652.1
VHLNM_198156.3 linkuse as main transcriptc.341-3275A>G intron_variant NP_937799.1
VHLNR_176335.1 linkuse as main transcriptn.670-2A>G splice_acceptor_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
VHLENST00000256474.3 linkuse as main transcriptc.341-2A>G splice_acceptor_variant 1 NM_000551.4 ENSP00000256474 P1P40337-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Von Hippel-Lindau syndrome Pathogenic:3
Pathogenic, reviewed by expert panelcurationClinGen VHL Variant Curation Expert Panel, ClinGenJun 25, 2024The 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). -
Pathogenic, no assertion criteria providedclinical testingGenomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of PhiladelphiaFeb 26, 2016- -
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 28, 2022Variant summary: VHL c.341-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3' canonical acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251496 control chromosomes (gnomAD). The variant, c.341-2A>G, has been reported in the literature in multiple individuals affected with pheochromocytoma and renal cell carcinoma (e.g. Dalgliesh_2010, Garcias-Donas_2013, Pandit_2016, Razafinjatovo_2016). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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. Based on the evidence outlined above, the variant was classified as pathogenic. -
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 21, 2022For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.341-2A nucleotide in the VHL gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 17024664). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 223194). Disruption of this splice site has been observed in individuals with unilateral pheochromocytoma (PMID: 27539324). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 1 of the VHL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in VHL are known to be pathogenic (PMID: 8956040, 12202531, 29891534, 31350093). -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster
Benign
1.0
D;D
GERP RS
5.0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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