VCV000127830.65 - ClinVar

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

Germline

Top reviewed classifications are shown here.

Submission summary:

23 submissions

23 submitters

5 conditions

Reviewed by expert panel

Benign

Jun 2024 by ClinGen VHL Va… FDA Recognized Database

for Von Hippel-Lindau syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 127830 Accession: VCV000127830.65

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.3 3: 10146644 (GRCh38) [ NCBI UCSC ] 3: 10188328 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Mar 9, 2016	Oct 20, 2024	Jun 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000551.4:c.463+8C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001354723.2:c.*18-3143C>T		intron variant
NM_198156.3:c.341-3143C>T		intron variant
NC_000003.12:g.10146644C>T
NC_000003.11:g.10188328C>T
NG_008212.3:g.10010C>T
NG_046756.1:g.4406C>T
LRG_322:g.10010C>T
LRG_322t1:c.463+8C>T

... more HGVS ... less HGVS

Protein change

Other names

IVS2+8C>T

Canonical SPDI

NC_000003.12:10146643:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

0.00020 (T)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00016

1000 Genomes Project 0.00020

Exome Aggregation Consortium (ExAC) 0.00046

The Genome Aggregation Database (gnomAD), exomes 0.00049

The Genome Aggregation Database (gnomAD) 0.00051

Trans-Omics for Precision Medicine (TOPMed) 0.00055

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00085

Links

ClinGen: CA020379 dbSNP: rs5030834 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
VHL		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	834	2006
LOC107303340	-	-	-	GRCh38	-	1117

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not specified	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Jul 31, 2024	RCV000115747.30
Von Hippel-Lindau syndrome	Benign (5)	reviewed by expert panel	Jun 25, 2024	RCV000123108.24
Hereditary cancer-predisposing syndrome	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Aug 5, 2021	RCV000210772.11
not provided	Conflicting interpretations of pathogenicity (9)	criteria provided, conflicting classifications	Mar 1, 2024	RCV000589592.44
Chuvash polycythemia Von Hippel-Lindau syndrome	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV001084968.16

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Benign (Jun 25, 2024)	reviewed by expert panel (ClinGen VHL VCEP ACMG Specifications VHL V1) Method: curation	Von Hippel-Lindau syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen VHL Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV005187298.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024	Publications: PubMed (1) PubMed: 9398721 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/aafdfd2b-5500-4e62-8d25-16de393ad917 Comment: 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 … (more) 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). (less)
Benign (Jan 13, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697517.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Publications: PubMed (6) PubMed: 15932632‚ 9663592‚ 9398721‚ 22799452‚ 23434161‚ 11409863 Comment: 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 … (more) 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. (less)
Uncertain significance (Aug 08, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Von Hippel-Lindau syndrome Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001304545.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 22799452‚ 9398721 Comment: 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, … (more) 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. (less)
benign (Mar 30, 2023)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004221483.2 First in ClinVar: Jan 06, 2024 Last updated: Sep 29, 2024	Comment: The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools … (more) The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing. This nucleotide position exhibits low evolutionary conservation. (less)
Likely benign (Feb 05, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Vantari Genetics Accession: SCV000267099.1 First in ClinVar: Apr 14, 2016 Last updated: Apr 14, 2016
Likely benign (Mar 28, 2016)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000540656.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or … (more) Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Outside splice consensus; 2 pubs in HGMD describe 1 proband with no segs (less) Method: Genome/Exome Filtration
Likely benign (Feb 17, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805351.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018
Likely benign (Aug 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002070985.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Likely benign (Feb 21, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002534176.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Uncertain significance (Nov 03, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011310.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Von Hippel-Lindau syndrome Chuvash polycythemia Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000166410.14 First in ClinVar: Jun 15, 2014 Last updated: Feb 28, 2024
Benign (Aug 05, 2021)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002636643.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 11409863‚ 22799452‚ 9398721‚ 9663592 Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Uncertain significance (Jul 31, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002552404.7 First in ClinVar: Jul 27, 2022 Last updated: Aug 04, 2024
Likely benign (Nov 01, 2017)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000149656.11 First in ClinVar: May 17, 2014 Last updated: Dec 19, 2017	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Likely benign (Sep 20, 2017)	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015)) Method: clinical testing	Von Hippel-Lindau syndrome Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000785566.2 First in ClinVar: Jul 01, 2016 Last updated: Jul 01, 2016	Publications: PubMed (6) PubMed: 9398721‚ 22799452‚ 11409863‚ 23434161‚ 27146957‚ 9663592
Likely benign (Mar 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001153780.27 First in ClinVar: Feb 03, 2020 Last updated: Oct 20, 2024	Comment: VHL: BP4 Number of individuals with the variant: 5
Likely benign (Feb 26, 2016)	no assertion criteria provided Method: clinical testing	Von Hippel-Lindau syndrome Affected status: unknown Allele origin: germline	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000264746.1 First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016	Number of individuals with the variant: 2
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808973.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Likely benign (Nov 22, 2018)	no assertion criteria provided (ACMG Guidelines, 2015) Method: clinical testing	Von Hippel-Lindau syndrome Affected status: unknown Allele origin: germline	Clinical Genomics Labs, University Health Network Accession: SCV001950149.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001956241.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001968532.1 First in ClinVar: Oct 08, 2021 Last updated: Oct 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001741627.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930615.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

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).

Comment:

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.

Comment:

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.

Comment:

The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing. This nucleotide position exhibits low evolutionary conservation.

Comment:

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Outside splice consensus; 2 pubs in HGMD describe 1 proband with no segs

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Germline variants in Hamartomatous Polyposis Syndrome-associated genes from patients with one or few hamartomatous polyps.	Jelsig AM	Scandinavian journal of gastroenterology	2016	PMID: 27146957
Sequence variations in the von Hippel-Lindau tumor suppressor gene in patients with intracranial aneurysms.	Klingler JH	Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association	2013	PMID: 23434161
Identification of 3 novel VHL germ-line mutations in Danish VHL patients.	Dandanell M	BMC medical genetics	2012	PMID: 22799452
Prevalence of von Hippel-Lindau gene mutations in sporadic renal cell carcinoma: results from The Netherlands cohort study.	van Houwelingen KP	BMC cancer	2005	PMID: 15932632
DHPLC-based germline mutation screening in the analysis of the VHL tumor suppressor gene: usefulness and limitations.	Klein B	Human genetics	2001	PMID: 11409863
Germline mutations in the vhl gene in patients presenting with phaeochromocytomas.	van der Harst E	International journal of cancer	1998	PMID: 9663592
Sporadic pheochromocytomas are rarely associated with germline mutations in the vhl tumor suppressor gene or the ret protooncogene.	Brauch H	The Journal of clinical endocrinology and metabolism	1997	PMID: 9398721
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/aafdfd2b-5500-4e62-8d25-16de393ad917	-	-	-	-

Text-mined citations for rs5030834 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs5030834 ...