The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computer assertion could be determined for this classification!


Variant: NM_000551.4(VHL):c.463+1G>A

CA16621909

526679 (ClinVar)

Gene: VHL
Condition: von Hippel-Lindau disease
Inheritance Mode: Autosomal dominant inheritance
UUID: 89c99594-21d8-4470-b028-29bdc82d3612
Approved on: 2024-06-25
Published on: 2024-06-25

HGVS expressions

NM_000551.4:c.463+1G>A
NM_000551.4(VHL):c.463+1G>A
NC_000003.12:g.10146637G>A
CM000665.2:g.10146637G>A
NC_000003.11:g.10188321G>A
CM000665.1:g.10188321G>A
NC_000003.10:g.10163321G>A
NG_008212.3:g.10003G>A
ENST00000696142.1:c.*140+1G>A
ENST00000696143.1:c.600-3150G>A
ENST00000696153.1:c.463+1G>A
ENST00000256474.3:c.463+1G>A
ENST00000256474.2:c.463+1G>A
ENST00000345392.2:c.341-3150G>A
ENST00000477538.1:n.599+1G>A
NM_000551.3:c.463+1G>A
NM_198156.2:c.341-3150G>A
NM_001354723.1:c.*18-3150G>A
NM_001354723.2:c.*18-3150G>A
NM_198156.3:c.341-3150G>A
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Pathogenic

Met criteria codes 3
PVS1_Strong PM2_Supporting PS4

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen VHL Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for VHL Version 1.0.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
VHL VCEP
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).
Met criteria codes
PVS1_Strong
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 to skip exon 2. There is a known non-functional naturally occurring isoform missing exon 2 (PMID: 29891534, 31350093).
PM2_Supporting
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 (due to a single variant present) (PM2_Supporting).
PS4
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) Invitae-1 Male, clinical dx of VHL; pt has had multiple hemangioblastomas and spinal tumors in 20’s. Father dx with VHL and paternal half siblings dx with VHL (Invitae internal data). 6 points, PS4.
Curation History
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