NM_000551.4(VHL):c.463+8C>T AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (9 submissions)
Last evaluated:: Mar 1, 2024
Review status:: criteria provided, conflicting classifications

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:: RCV000589592.44

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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ribonuclease 7 precursor [Homo sapiens]
ribonuclease 7 precursor [Homo sapiens]
gi|1519315756|ref|NP_115961.3|

Protein
C962R [African swine fever virus]
C962R [African swine fever virus]
gi|783806627|gb|AJZ77047.1|

Protein
AEP1 [Saccharomyces cerevisiae]
AEP1 [Saccharomyces cerevisiae]
gi|3349|emb|CAA40367.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000697517	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Benign (Jan 13, 2016)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15932632, 9663592, 9398721, 22799452, 23434161, 11409863 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000805351	PreventionGenetics, part of Exact Sciences	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Feb 17, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001153780	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Likely benign (Mar 1, 2024)	germline	clinical testing	Citation Link,
SCV001741627	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001808973	Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001930615	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001956241	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV001968532	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely benign	germline	clinical testing
SCV002011310	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 3, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Prevalence of von Hippel-Lindau gene mutations in sporadic renal cell carcinoma: results from The Netherlands cohort study.

van Houwelingen KP, van Dijk BA, Hulsbergen-van de Kaa CA, Schouten LJ, Gorissen HJ, Schalken JA, van den Brandt PA, Oosterwijk E.

BMC Cancer. 2005 Jun 2;5:57.

PubMed [citation]

PMID:: 15932632
PMCID:: PMC1177929

Germline mutations in the vhl gene in patients presenting with phaeochromocytomas.

van der Harst E, de Krijger RR, Dinjens WN, Weeks LE, Bonjer HJ, Bruining HA, Lamberts SW, Koper JW.

Int J Cancer. 1998 Jul 29;77(3):337-40.

PubMed [citation]

PMID:: 9663592

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697517.1

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

Description

Variant summary: Variant of interest is a substitution of a non-conserved nucleotide located at an intronic position not widely known to affect splicing. 5/5 in silico tools via Alamut predict no impact on normal splicing by the variant along with mutation taster predicting a neutral outcome. The variant was found in the European and African subcohorts of the ExAC project at an allele frequency of 0.076% and 0.048% respectively. These allele frequencies exceed the maximal expected allele frequency of a disease causing VHL variant (0.0028%) indicating the variant to be non-disease causing. It was also seen in patients with phaeochromocytoma, suspected VHL disease and with sporadic RCC, however without strong evidence for pathogenicity. Multiple clinical diagnostic laboratories classify variant as Likely Benign/Benign via ClinVar (without evidence to independently evaluate). Considering the high prevalence of the variant in the general population this variant is classified as benign.

#	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 PreventionGenetics, part of Exact Sciences, SCV000805351.1

#	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 CeGaT Center for Human Genetics Tuebingen, SCV001153780.27

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	5	not provided	not provided	clinical testing	not provided

Description

VHL: BP4

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		5	not provided	not provided	not provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001741627.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, Amsterdam University Medical Center - VKGL Data-share Consensus, SCV001808973.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001930615.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001956241.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001968532.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden, SCV002011310.3

#	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	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

Relating variation to medicine