VCV000137905.19 - ClinVar

NM_000551.4(VHL):c.246C>T (p.Arg82=)

Germline

Top reviewed classifications are shown here.

Submission summary:

9 submissions

9 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.246C>T (p.Arg82=)

Variation ID: 137905 Accession: VCV000137905.19

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.3 3: 10142093 (GRCh38) [ NCBI UCSC ] 3: 10183777 (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	Jan 31, 2016	Aug 18, 2024	Jun 25, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000551.4:c.246C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000542.1:p.Arg82=	synonymous
NM_001354723.2:c.246C>T	NP_001341652.1:p.Arg82=	synonymous
NM_198156.3:c.246C>T	NP_937799.1:p.Arg82=	synonymous
NC_000003.12:g.10142093C>T
NC_000003.11:g.10183777C>T
NG_008212.3:g.5459C>T
LRG_322:g.5459C>T
LRG_322t1:c.246C>T	LRG_322p1:p.Arg82=

... more HGVS ... less HGVS

Protein change

Other names

p.R82R:CGC>CGT
NM_000551.4(VHL):c.246C>T
p.Arg82=

Canonical SPDI

NC_000003.12:10142092: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.

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

Exome Aggregation Consortium (ExAC) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00010

The Genome Aggregation Database (gnomAD) 0.00014

Trans-Omics for Precision Medicine (TOPMed) 0.00014

Links

ClinGen: CA020164 dbSNP: rs587780993 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	832	2004

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.
Hereditary cancer-predisposing syndrome	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	May 21, 2021	RCV000126301.9
not specified	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jul 31, 2024	RCV000213078.2
Von Hippel-Lindau syndrome	Benign (3)	reviewed by expert panel	Jun 25, 2024	RCV000206706.6
not provided	Likely benign (1)	criteria provided, single submitter	Dec 14, 2016	RCV000679025.7
Chuvash polycythemia Von Hippel-Lindau syndrome	Likely benign (1)	criteria provided, single submitter	Feb 1, 2024	RCV001084263.8

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: SCV005187311.1 First in ClinVar: Aug 18, 2024 Last updated: Aug 18, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4d337c56-d3e7-4abc-8cd9-ec05060ab40d Comment: The variant NM_000551.4(VHL):c.246C>T (p.Arg82=) is a synonymous (silent) variant that does not display splicing impact according to SpliceAI and VarSeak (BP4). The GroupMax Filtering Allele … (more) The variant NM_000551.4(VHL):c.246C>T (p.Arg82=) is a synonymous (silent) variant that does not display splicing impact according to SpliceAI and VarSeak (BP4). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0002832 (365/1179692 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). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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 (Feb 14, 2014)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000169802.11 First in ClinVar: Jun 23, 2014 Last updated: Jun 01, 2016	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 (Dec 14, 2016)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000805332.1 First in ClinVar: Sep 14, 2018 Last updated: Sep 14, 2018
Benign (May 21, 2021)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002534151.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Likely benign (Dec 01, 2015)	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: SCV000487851.2 First in ClinVar: Jan 31, 2016 Last updated: Dec 24, 2022
Likely benign (Feb 01, 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: SCV000259741.10 First in ClinVar: Jan 31, 2016 Last updated: Feb 28, 2024
Likely Benign (Feb 05, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Von Hippel-Lindau syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	All of Us Research Program, National Institutes of Health Accession: SCV004841641.1 First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 Comment: This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of … (more) This study involves interpretation of variants in research participants for the purpose of population health screening. Participant phenotype was not available at the time of variant classification. Additional details can be found in publication PMID: 35346344, PMCID: PMC8962531 (less)	Number of individuals with the variant: 45
Likely benign (Aug 31, 2015)	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: SCV000213943.7 First in ClinVar: Mar 24, 2015 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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)
Likely benign (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: SCV005090546.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024

Comment:

The variant NM_000551.4(VHL):c.246C>T (p.Arg82=) is a synonymous (silent) variant that does not display splicing impact according to SpliceAI and VarSeak (BP4). The GroupMax Filtering Allele Frequency (95% CI) in gnomAD v4.1.0 is 0.0002832 (365/1179692 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). In summary, this variant meets the criteria to be classified as Benign for autosomal-dominant von Hippel Lindau syndrome (VHL syndrome) 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:

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.

Comment:

This alteration is classified as likely 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.

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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4d337c56-d3e7-4abc-8cd9-ec05060ab40d	-	-	-	-

Text-mined citations for rs587780993 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000551.4(VHL):c.246C>T (p.Arg82=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs587780993 ...