VCV000223170.14 - ClinVar

NM_000551.4(VHL):c.257C>G (p.Pro86Arg)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

6 out of 7 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000551.4(VHL):c.257C>G (p.Pro86Arg)

Variation ID: 223170 Accession: VCV000223170.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.3 3: 10142104 (GRCh38) [ NCBI UCSC ] 3: 10183788 (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	Feb 23, 2026	Jul 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000551.4:c.257C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000542.1:p.Pro86Arg	missense
NM_001354723.2:c.257C>G	NP_001341652.1:p.Pro86Arg	missense
NM_198156.3:c.257C>G	NP_937799.1:p.Pro86Arg	missense
NC_000003.12:g.10142104C>G
NC_000003.11:g.10183788C>G
NG_008212.3:g.5470C>G
LRG_322:g.5470C>G
LRG_322t1:c.257C>G	LRG_322p1:p.Pro86Arg
	P40337:p.Pro86Arg

... more HGVS ... less HGVS

Protein change

P86R

Other names

Canonical SPDI

NC_000003.12:10142103:C:G

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.

Links

ClinGen: CA357142 UniProtKB: P40337#VAR_005695 dbSNP: rs730882034 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	954	2251

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.
Von Hippel-Lindau syndrome	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 1, 2016	RCV000208868.9
Chuvash polycythemia Von Hippel-Lindau syndrome	Pathogenic (1)	criteria provided, single submitter	Jul 11, 2024	RCV000631258.16
Hereditary cancer-predisposing syndrome	Pathogenic (1)	criteria provided, single submitter	Jul 28, 2023	RCV002426981.10
not provided	Pathogenic/Likely pathogenic (2)	criteria provided, multiple submitters, no conflicts	Apr 19, 2023	RCV003237772.10

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.	Expand all rows Collapse all rows 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.
Pathogenic (Feb 02, 2016) C Contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Von Hippel-Lindau syndrome	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000697491.1 First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016	Publications: PubMed (4) PubMed: 11114638‚ 11257211‚ 17024664‚ 9829911 Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Nov 01, 2016) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Von Hippel-Lindau syndrome	Center for Human Genetics, Inc, Center for Human Genetics, Inc Accession: SCV000782418.1 First in ClinVar: May 03, 2018 Last updated: May 03, 2018	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Nov 03, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002011312.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided

Pathogenic (Jul 28, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Hereditary cancer-predisposing syndrome	Ambry Genetics Accession: SCV002740355.3 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Publications: PubMed (4) PubMed: 11257211‚ 17024664‚ 29595810‚ 9829911 Comment: show The p.P86R pathogenic mutation (also known as c.257C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 257. The proline at codon 86 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in numerous families with a diagnosis of Von Hippel-Lindau syndrome (VHL) (Stolle C et al. Hum. Mutat. 1998;12:417-23; Rothberg PG et al. Mol. Diagn. 2001 Mar;6:49-54; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Liu SJ et al. Genet. Med. 2018 10;20:1266-1273). Of note, the p.P86L (c.257C>T) alteration has also been reported as p.P157L (c.470C>T) in some literature. Several other alterations at the same codon (p.P86A, p.P86L, and p.P86S) have been detected in individuals with VHL syndrome suggesting this codon may represent a mutation hotspot. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jul 11, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	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.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000752286.6 First in ClinVar: May 28, 2018 Last updated: Feb 23, 2026	Publications: PubMed (10) PubMed: 10205047‚ 11257211‚ 17024664‚ 19408298‚ 22799452‚ 27034144‚ 27057652‚ 27527340‚ 9829911‚ 9829912 Comment: show This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 86 of the VHL protein (p.Pro86Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 9829911, 11257211, 17024664, 19408298). ClinVar contains an entry for this variant (Variation ID: 223170). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9829912, 10205047, 22799452, 27034144, 27057652, 27527340). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely pathogenic (Apr 19, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004226809.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (11) PubMed: 10761708‚ 15918937‚ 17688370‚ 18836774‚ 19408298‚ 19464396‚ 24335534‚ 27179072‚ 29595810‚ 29748190‚ 7728151 Comment: show PP3, PP4, PM1, PM2, PM5 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Number of individuals with the variant: 2

Likely pathogenic (Feb 26, 2016) N Not contributing to aggregate classification	no assertion criteria provided	Von Hippel-Lindau syndrome	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia Accession: SCV000264686.1 First in ClinVar: Mar 09, 2016 Last updated: Mar 09, 2016	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 3

Comment:

The p.P86R pathogenic mutation (also known as c.257C>G), located in coding exon 1 of the VHL gene, results from a C to G substitution at nucleotide position 257. The proline at codon 86 is replaced by arginine, an amino acid with dissimilar properties. This variant has been reported in numerous families with a diagnosis of Von Hippel-Lindau syndrome (VHL) (Stolle C et al. Hum. Mutat. 1998;12:417-23; Rothberg PG et al. Mol. Diagn. 2001 Mar;6:49-54; Ong KR et al. Hum. Mutat. 2007 Feb;28:143-9; Liu SJ et al. Genet. Med. 2018 10;20:1266-1273). Of note, the p.P86L (c.257C>T) alteration has also been reported as p.P157L (c.470C>T) in some literature. Several other alterations at the same codon (p.P86A, p.P86L, and p.P86S) have been detected in individuals with VHL syndrome suggesting this codon may represent a mutation hotspot. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

Comment:

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 86 of the VHL protein (p.Pro86Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with von Hippel-Lindau syndrome (PMID: 9829911, 11257211, 17024664, 19408298). ClinVar contains an entry for this variant (Variation ID: 223170). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function with a positive predictive value of 95%. This variant disrupts the p.Pro86 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9829912, 10205047, 22799452, 27034144, 27057652, 27527340). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.	Krauss T	Endocrine-related cancer	2018	PMID: 29748190
Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein.	Liu SJ	Genetics in medicine : official journal of the American College of Medical Genetics	2018	PMID: 29595810
Clinical and molecular characteristics of East Asian patients with von Hippel-Lindau syndrome.	Wong M	Chinese journal of cancer	2016	PMID: 27527340
Aggregation dynamics and identification of aggregation-prone mutants of the von Hippel-Lindau tumor suppressor protein.	Le Goff X	Journal of cell science	2016	PMID: 27179072
Germline mutations in the VHL gene associated with 3 different renal lesions in a Chinese von Hippel-Lindau disease family.	Yuan P	Cancer biology & therapy	2016	PMID: 27057652
Coexistence of VHL Disease and CPT2 Deficiency: A Case Report.	Ferrara AM	Cancer research and treatment	2016	PMID: 27034144
Molecular dissection of the VHL gene in solitary capillary hemangioblastoma of the central nervous system.	Muscarella LA	Journal of neuropathology and experimental neurology	2014	PMID: 24335534
Identification of 3 novel VHL germ-line mutations in Danish VHL patients.	Dandanell M	BMC medical genetics	2012	PMID: 22799452
Germline mutations in the von Hippel-Lindau gene in Italian patients.	Ciotti P	European journal of medical genetics	2009	PMID: 19464396
Structural bioinformatics mutation analysis reveals genotype-phenotype correlations in von Hippel-Lindau disease and suggests molecular mechanisms of tumorigenesis.	Forman JR	Proteins	2009	PMID: 19408298
Computational detection of deleterious SNPs and their effect on sequence and structural level of the VHL gene.	Rajasekaran R	Mammalian genome : official journal of the International Mammalian Genome Society	2008	PMID: 18836774
Germline VHL gene mutations in three Serbian families with von Hippel-Lindau disease.	Stanojevic BR	Neoplasma	2007	PMID: 17688370
Genotype-phenotype correlations in von Hippel-Lindau disease.	Ong KR	Human mutation	2007	PMID: 17024664
Hemangioblastomas of central nervous system: molecular genetic analysis and clinical management.	Catapano D	Neurosurgery	2005	PMID: 15918937
Is the P25L a "real" VHL mutation?	Rothberg PG	Molecular diagnosis : a journal devoted to the understanding of human disease through the clinical application of molecular biology	2001	PMID: 11257211
Clinical and genetic analysis of patients with pancreatic neuroendocrine tumors associated with von Hippel-Lindau disease.	Libutti SK	Surgery	2000	PMID: 11114638
Germ-line mutation analysis in patients with von Hippel-Lindau disease in Japan: an extended study of 77 families.	Yoshida M	Japanese journal of cancer research : Gann	2000	PMID: 10761708
Structure of the VHL-ElonginC-ElonginB complex: implications for VHL tumor suppressor function.	Stebbins CE	Science (New York, N.Y.)	1999	PMID: 10205047
Germline mutation profile of the VHL gene in von Hippel-Lindau disease and in sporadic hemangioblastoma.	Olschwang S	Human mutation	1998	PMID: 9829912
Improved detection of germline mutations in the von Hippel-Lindau disease tumor suppressor gene.	Stolle C	Human mutation	1998	PMID: 9829911
Germline mutations in the von Hippel-Lindau disease tumor suppressor gene: correlations with phenotype.	Chen F	Human mutation	1995	PMID: 7728151
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Text-mined citations for rs730882034 ...

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 Feb 24, 2026