Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Clin |
RCV004691263 | SCV005187301 | pathogenic | Von Hippel-Lindau syndrome | 2024-06-25 | reviewed by expert panel | curation | 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). |
| Labcorp Genetics |
RCV000631276 | SCV000752304 | pathogenic | Chuvash polycythemia; Von Hippel-Lindau syndrome | 2023-04-07 | criteria provided, single submitter | clinical testing | 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). |
| Athena Diagnostics | RCV000714168 | SCV000844854 | pathogenic | not provided | 2015-03-31 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002334057 | SCV002636641 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-05-12 | criteria provided, single submitter | clinical testing | 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. |