NM_000551.4(VHL):c.461C>T (p.Pro154Leu) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 1, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000804483.7

Allele description [Variation Report for NM_000551.4(VHL):c.461C>T (p.Pro154Leu)]

NM_000551.4(VHL):c.461C>T (p.Pro154Leu)

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.461C>T (p.Pro154Leu)

HGVS:

NC_000003.12:g.10146634C>T
NG_008212.3:g.10000C>T
NG_046756.1:g.4396C>T
NM_000551.4:c.461C>TMANE SELECT
NM_001354723.2:c.*18-3153C>T
NM_198156.3:c.341-3153C>T
NP_000542.1:p.Pro154Leu
NP_000542.1:p.Pro154Leu
LRG_322t1:c.461C>T
LRG_322:g.10000C>T
LRG_322p1:p.Pro154Leu
NC_000003.11:g.10188318C>T
NM_000551.3:c.461C>T

Protein change:

P154L

Links:

dbSNP: rs1399097617

NCBI 1000 Genomes Browser:

rs1399097617

Molecular consequence:

NM_001354723.2:c.*18-3153C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3153C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.461C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Chuvash polycythemia
Synonyms:: POLYCYTHEMIA, VHL-DEPENDENT; Erythrocytosis, familial, 2
Identifiers:: MONDO: MONDO:0009892; MedGen: C1837915; Orphanet: 238557; OMIM: 263400

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000944394	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 1, 2018)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 14556007, 20660572, 23143947, 7987306, 25867206, 17024664, 8956040, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000944394

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 1, 2018)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Tat-binding protein-1, a component of the 26S proteasome, contributes to the E3 ubiquitin ligase function of the von Hippel-Lindau protein.

Corn PG, McDonald ER 3rd, Herman JG, El-Deiry WS.

Nat Genet. 2003 Nov;35(3):229-37. Epub 2003 Oct 12.

PubMed [citation]

PMID:: 14556007

Systematic comparison of sporadic and syndromic pancreatic islet cell tumors.

Erlic Z, Ploeckinger U, Cascon A, Hoffmann MM, von Duecker L, Winter A, Kammel G, Bacher J, Sullivan M, Isermann B, Fischer L, Raffel A, Knoefel WT, Schott M, Baumann T, Schaefer O, Keck T, Baum RP, Milos I, Muresan M, Peczkowska M, Januszewicz A, et al.

Endocr Relat Cancer. 2010 Oct 5;17(4):875-83. doi: 10.1677/ERC-10-0037. Print 2010 Dec.

PubMed [citation]

PMID:: 20660572

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000944394.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this missense change affects HIF1 alpha degradation due to a reduced interaction with TBP1 and the proteasome (PMID: 14556007). This variant has been observed in several individuals and families affected with von Hippel-Lindau syndrome (PMID: 20660572, 23143947, 7987306, 25867206, 17024664, 8956040). This variant is also known as c.674C>T (p.Pro225Leu) in the literature. This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with leucine at codon 154 of the VHL protein (p.Pro154Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine.

#	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

Last Updated: Sep 29, 2024

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