NM_000551.4:c.463+1G>A

Variant names:

• chr3-10146637-G-A
• rs869025657
• NM_000551.4:c.463+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2_Supporting PVS1_Strong PS4

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:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: VHL NM_000551.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.68
• Publications: 1 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 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	NM_000551.4	MANE Select	c.463+1G>A		splice_donor intron	N/A	NP_000542.1
	VHL	NM_001354723.2		c.*18-3150G>A		intron	N/A	NP_001341652.1
	VHL	NM_198156.3		c.341-3150G>A		intron	N/A	NP_937799.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VHL	ENST00000256474.3	TSL:1 MANE Select	c.463+1G>A		splice_donor intron	N/A	ENSP00000256474.3
	VHL	ENST00000345392.3	TSL:1	c.341-3150G>A		intron	N/A	ENSP00000344757.2
	VHL	ENST00000477538.2	TSL:1	n.1343+1G>A		splice_donor intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461302 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726970

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53360

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111612

Other (OTH) AF: 0.0000166 AC: 1 AN: 60342

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)
1	-	-	Von Hippel-Lindau syndrome (1)
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	Pathogenic	0.33
CADD	Pathogenic	35
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.97	D
PhyloP100		7.7
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.49		Position offset: 39
DS_DL_spliceai		0.96		Position offset: -1

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

Other links and lift over

dbSNP: rs869025657; hg19: chr3-10188321; COSMIC: COSV56543633;