rs869025657
Variant summary
Our verdict is Pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_StrongPM2_SupportingPS4
This summary comes from the ClinGen Evidence Repository: The variant NM_000551.3(VHL):c.463+1G>A is a canonical splice site within the 2nd intron of the VHL gene. If a cryptic splice does not alter the reading frame, and is in a critical domain (AA 63-204), it can receive PVS1_Strong . Exon 2 is an in-frame exon (AA 114-156). Disruption of the splice donor site by this variant may cause skipping of exon 2. There is a known non-functional naturally occurring isoform missing exon 2 (PMID:29891534, 31350093). (PVS1_Strong). There is one variant present in gnomAD v4.1.0. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is not calculated. PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD, or if no GroupMax Filtering Allele Frequency is calculated (PM2_Supporting). Multiple cases are reported in the literature as follows: Case 1) a Japanese VHL family (table 1): retinal angioma, CNS hemangioblastoma, pancreatic cyst/tumor, RCC, Described as c.676+1G>A (PMID:10761708) Case 2) South American VHL cohort, and variant described as IVS2+1G>A in a family with 5 affected members (table 1, PMID:8956040 cited): CNS hemangioblastoma; retinal angioma; renal carcinoma; pancreatic cystadenoma (PMID:12624160) Case 3) French VHL Study Group. The patient (no 23 from family 582) presented with pancreatic endocrine tumour and renal carcinoma (PMID:18580449) Case 4) Brazilian patients. The patient, age 45, presented with renal cyst, pancreatic cyst and CNS hemangioblastoma (PMID:31528828) Case 5) Italian patients. Found in one patient. Clinical manifestations include CNS hemangioblastoma, retinal hemangioblastoma, pancreatic cysts, and ovarian cysts (PMID:19464396) Case 6) Male, clinical dx of VHL; multiple hemangioblastomas and spinal tumors in 20’s. Father and paternal half-siblings dx with VHL. (6 points, PS4). 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/CA16621909/MONDO:0008667/078
Frequency
Consequence
NM_000551.4 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| VHL | NM_000551.4 | c.463+1G>A | splice_donor_variant | ENST00000256474.3 | NP_000542.1 | |||
| VHL | NM_001354723.2 | c.*18-3150G>A | intron_variant | NP_001341652.1 | ||||
| VHL | NM_198156.3 | c.341-3150G>A | intron_variant | NP_937799.1 | ||||
| VHL | NR_176335.1 | n.792+1G>A | splice_donor_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| VHL | ENST00000256474.3 | c.463+1G>A | splice_donor_variant | 1 | NM_000551.4 | ENSP00000256474 | P1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461302Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726970
GnomAD4 genome
ClinVar
Submissions by phenotype
Von Hippel-Lindau syndrome Pathogenic:1
| Pathogenic, reviewed by expert panel | curation | ClinGen VHL Variant Curation Expert Panel, ClinGen | Jun 25, 2024 | The variant NM_000551.3(VHL):c.463+1G>A is a canonical splice site within the 2nd intron of the VHL gene. If a cryptic splice does not alter the reading frame, and is in a critical domain (AA 63-204), it can receive PVS1_Strong . Exon 2 is an in-frame exon (AA 114-156). Disruption of the splice donor site by this variant may cause skipping of exon 2. There is a known non-functional naturally occurring isoform missing exon 2 (PMID: 29891534, 31350093). (PVS1_Strong). There is one variant present in gnomAD v4.1.0. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is not calculated. PM2_Supporting can be applied for variants with <= 0.0000015 (0.00015%) frequency in gnomAD, or if no GroupMax Filtering Allele Frequency is calculated (PM2_Supporting). Multiple cases are reported in the literature as follows: Case 1) a Japanese VHL family (table 1): retinal angioma, CNS hemangioblastoma, pancreatic cyst/tumor, RCC, Described as c.676+1G>A (PMID: 10761708) Case 2) South American VHL cohort, and variant described as IVS2+1G>A in a family with 5 affected members (table 1, PMID: 8956040 cited): CNS hemangioblastoma; retinal angioma; renal carcinoma; pancreatic cystadenoma (PMID: 12624160) Case 3) French VHL Study Group. The patient (no 23 from family 582) presented with pancreatic endocrine tumour and renal carcinoma (PMID: 18580449) Case 4) Brazilian patients. The patient, age 45, presented with renal cyst, pancreatic cyst and CNS hemangioblastoma (PMID: 31528828) Case 5) Italian patients. Found in one patient. Clinical manifestations include CNS hemangioblastoma, retinal hemangioblastoma, pancreatic cysts, and ovarian cysts (PMID: 19464396) Case 6) Male, clinical dx of VHL; multiple hemangioblastomas and spinal tumors in 20’s. Father and paternal half-siblings dx with VHL. (6 points, PS4). 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). - |
Von Hippel-Lindau syndrome;C1837915:Chuvash polycythemia Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 07, 2023 | This sequence change affects a donor splice site in intron 2 of the VHL gene. While this variant is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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: 526679). Disruption of this splice site has been observed in individuals with von Hippel-Lindau syndrome (PMID: 8707293, 10761708, 12624160, 21362373). This variant is not present in population databases (gnomAD no frequency). - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 31, 2015 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 12, 2022 | The c.463+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 2 of the VHL gene. This mutation has been identified in multiple individuals with Von Hippel-Lindau disease (VHL) (Yoshida et. al., Jpn J Cancer Res. 2000; 91(2): 204-12; Ciotti P et al Eur J Med Genet. 2009 Sep-Oct;52(5):311-4; Rocha JC et al. J. Med. Genet., 2003 Mar;40:e31; Ambry internal data). Of note, this mutation is also known as c.676+1G>A and IVS2+1G>A in published literature. In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at