NM_000551.4(VHL):c.463+8C>T AND Von Hippel-Lindau syndrome

Germline classification:: Benign (5 submissions)
Last evaluated:: Jun 25, 2024
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000123108.24

Allele description [Variation Report for NM_000551.4(VHL):c.463+8C>T]

NM_000551.4(VHL):c.463+8C>T

Genes:

LOC107303340:3p25 von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase Alu-mediated recombination region [Gene]
VHL:von Hippel-Lindau tumor suppressor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.463+8C>T

Other names:

IVS2+8C>T

HGVS:

NC_000003.12:g.10146644C>T
NG_008212.3:g.10010C>T
NG_046756.1:g.4406C>T
NM_000551.4:c.463+8C>TMANE SELECT
NM_001354723.2:c.*18-3143C>T
NM_198156.3:c.341-3143C>T
LRG_322t1:c.463+8C>T
LRG_322:g.10010C>T
NC_000003.11:g.10188328C>T
NM_000551.2:c.463+8C>T
NM_000551.3:c.463+8C>T

Links:

dbSNP: rs5030834

NCBI 1000 Genomes Browser:

rs5030834

Molecular consequence:

NM_000551.4:c.463+8C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001354723.2:c.*18-3143C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3143C>T - intron variant - [Sequence Ontology: SO:0001627]

Observations:

Condition(s)

Name:: Von Hippel-Lindau syndrome (VHLS)
Synonyms:: VHL syndrome; Von Hippel-Lindau
Identifiers:: MONDO: MONDO:0008667; MedGen: C0019562; Orphanet: 892; OMIM: 193300

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000264746	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	no assertion criteria provided	Likely benign (Feb 26, 2016)	germline	clinical testing
SCV000785566	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely benign (Sep 20, 2017)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9398721, 22799452, 11409863, 23434161, 27146957, 9663592 Counsyl_Autosomal_Dominant_Disease_Classification_criteria_(2015)_v1.pdf, Citation Link,
SCV001304545	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Aug 8, 2018)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22799452, 9398721 Citation Link,
SCV001950149	Clinical Genomics Labs, University Health Network	no assertion criteria provided (ACMG Guidelines, 2015)	Likely benign (Nov 22, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005187298	ClinGen VHL Variant Curation Expert Panel, ClinGen	reviewed by expert panel (ClinGen VHL VCEP ACMG Specifications VHL V1)	Benign (Jun 25, 2024)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

DHPLC-based germline mutation screening in the analysis of the VHL tumor suppressor gene: usefulness and limitations.

Klein B, Weirich G, Brauch H.

Hum Genet. 2001 May;108(5):376-84.

PubMed [citation]

PMID:: 11409863

Sequence variations in the von Hippel-Lindau tumor suppressor gene in patients with intracranial aneurysms.

Klingler JH, Krüger MT, Lemke JR, Jilg C, Van Velthoven V, Zentner J, Neumann HP, Gläsker S.

J Stroke Cerebrovasc Dis. 2013 May;22(4):437-43. doi: 10.1016/j.jstrokecerebrovasdis.2013.01.016. Epub 2013 Feb 20.

PubMed [citation]

PMID:: 23434161

See all PubMed Citations (7)

Details of each submission

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000264746.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Counsyl, SCV000785566.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Illumina Laboratory Services, Illumina, SCV001304545.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genomics Labs, University Health Network, SCV001950149.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen VHL Variant Curation Expert Panel, ClinGen, SCV005187298.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (1)

Description

The variant NM_000551.4(VHL):c.463+8C>T is an intronic variant. The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.001101 (1359/1179388 from European, Non-Finnish Population). This is higher than the ClinGen VHL VCEP threshold of >=0.000156 (0.0156%) threshold expected for VHL disease (BA1). Therefore this variant meets the criterion for (BA1) and is classified as Benign 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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