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NM_000551.4(VHL):c.250G>C (p.Val84Leu) AND Von Hippel-Lindau syndrome

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Aug 1, 2018
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV000588802.2

Allele description [Variation Report for NM_000551.4(VHL):c.250G>C (p.Val84Leu)]

NM_000551.4(VHL):c.250G>C (p.Val84Leu)

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.250G>C (p.Val84Leu)
HGVS:
  • NC_000003.12:g.10142097G>C
  • NG_008212.3:g.5463G>C
  • NM_000551.4:c.250G>CMANE SELECT
  • NM_001354723.2:c.250G>C
  • NM_198156.3:c.250G>C
  • NP_000542.1:p.Val84Leu
  • NP_000542.1:p.Val84Leu
  • NP_001341652.1:p.Val84Leu
  • NP_937799.1:p.Val84Leu
  • LRG_322t1:c.250G>C
  • LRG_322:g.5463G>C
  • LRG_322p1:p.Val84Leu
  • NC_000003.11:g.10183781G>C
  • NM_000551.3:c.250G>C
  • P40337:p.Val84Leu
Protein change:
V84L
Links:
UniProtKB: P40337#VAR_005692; dbSNP: rs5030827
NCBI 1000 Genomes Browser:
rs5030827
Molecular consequence:
  • NM_000551.4:c.250G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354723.2:c.250G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.250G>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
3

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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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000697488Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Pathogenic
(Jan 29, 2016) 		germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx,

Citation Link,

SCV000897790Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
criteria provided, single submitter

(DGD Variant Analysis Guidelines)		Pathogenic
(Aug 1, 2018) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlineyes3not providednot providednot providednot providedclinical testing

Citations

PubMed

Differences in regulation of tight junctions and cell morphology between VHL mutations from disease subtypes.

Bangiyeva V, Rosenbloom A, Alexander AE, Isanova B, Popko T, Schoenfeld AR.

BMC Cancer. 2009 Jul 14;9:229. doi: 10.1186/1471-2407-9-229.

PubMed [citation]
PMID:
19602254
PMCID:
PMC2722669

Integrative genomic analysis reveals somatic mutations in pheochromocytoma and paraganglioma.

Burnichon N, Vescovo L, Amar L, Libé R, de Reynies A, Venisse A, Jouanno E, Laurendeau I, Parfait B, Bertherat J, Plouin PF, Jeunemaitre X, Favier J, Gimenez-Roqueplo AP.

Hum Mol Genet. 2011 Oct 15;20(20):3974-85. doi: 10.1093/hmg/ddr324. Epub 2011 Jul 22.

PubMed [citation]
PMID:
21784903
See all PubMed Citations (5)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697488.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

Variant summary: This c.250G>C variant affects a conserved nucleotide, resulting in amino acid change from Val to Leu in beta domain of VHL protein. 2/4 in-silico tools predict this variant to be damaging. This variant was not found in approximately 99326 chromosomes from ExAC. This variant has been reported in one VHL patient as a de novo occurrence (Leonardi_2011) and in other two VHL patients as somatic occurrence (Burnichon_2011, Pena-Llopis_2013). Another nucleotide change c.250G>T leading to the same amino acid change is a known pathogenic variant, strongly supporting that this nucleotide change is also pathogenic. Functional studies show that p.V84L mutant impairs in forming stable pVHL-ElonginC-ElonginB (VCB) complexes which is implicated in the disease (Knauth_2009). Taken together, this variant has been classified as a Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000897790.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided3not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided3not providednot providednot provided

Last Updated: Sep 29, 2024