NM_000551.4(VHL):c.242C>T (p.Pro81Leu) AND Von Hippel-Lindau syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Likely pathogenic (5 submissions)
Last evaluated:: Apr 27, 2023
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:: RCV000030582.10

Allele description

NM_000551.4(VHL):c.242C>T (p.Pro81Leu)

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.242C>T (p.Pro81Leu)

HGVS:

NC_000003.12:g.10142089C>T
NG_008212.3:g.5455C>T
NM_000551.4:c.242C>TMANE SELECT
NM_001354723.2:c.242C>T
NM_198156.3:c.242C>T
NP_000542.1:p.Pro81Leu
NP_000542.1:p.Pro81Leu
NP_001341652.1:p.Pro81Leu
NP_937799.1:p.Pro81Leu
LRG_322t1:c.242C>T
LRG_322:g.5455C>T
LRG_322p1:p.Pro81Leu
NC_000003.11:g.10183773C>T
NM_000551.3:c.242C>T
p.P81L
p.[Pro81Leu]

Protein change:

P81L

Links:

dbSNP: rs193922608

NCBI 1000 Genomes Browser:

rs193922608

Molecular consequence:

NM_000551.4:c.242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.242C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.242C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000053258	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	likely pathogenic (Aug 18, 2011)	germline	curation	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000264681	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	no assertion criteria provided	Likely pathogenic (Feb 26, 2016)	germline	clinical testing
SCV002601728	Clinical Genomics Labs, University Health Network	no assertion criteria provided (ACMG Guidelines, 2015)	Likely pathogenic (Feb 21, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004183372	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Mar 31, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004841640	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely Pathogenic (Apr 27, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17102082, 21389259, 22241717, 24134185, 33219105, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing, curation
not provided	germline	unknown	11	not provided	not provided	108544	not provided	clinical testing

Citations

PubMed

Genetic mutation screening in an italian cohort of nonsyndromic pheochromocytoma/paraganglioma patients.

Castellano M, Mori L, Giacchè M, Agliozzo E, Tosini R, Panarotto A, Cappelli C, Mulatero P, Cumetti D, Veglio F, Agabiti-Rosei E.

Ann N Y Acad Sci. 2006 Aug;1073:156-65.

PubMed [citation]

PMID:: 17102082

Cardiopulmonary function in two human disorders of the hypoxia-inducible factor (HIF) pathway: von Hippel-Lindau disease and HIF-2alpha gain-of-function mutation.

Formenti F, Beer PA, Croft QP, Dorrington KL, Gale DP, Lappin TR, Lucas GS, Maher ER, Maxwell PH, McMullin MF, O'Connor DF, Percy MJ, Pugh CW, Ratcliffe PJ, Smith TG, Talbot NP, Robbins PA.

FASEB J. 2011 Jun;25(6):2001-11. doi: 10.1096/fj.10-177378. Epub 2011 Mar 9.

PubMed [citation]

PMID:: 21389259
PMCID:: PMC3159892

See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000053258.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	curation	PubMed (1)

Description

"Authors do not mention testing for this variant in normal controls": PubMed [ID: 17102082]

Description

Converted during submission to Likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		1	not provided	not provided	not provided

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000264681.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	10	not provided	not provided	clinical testing	not provided

#	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		10	not provided	not provided	not provided

From Clinical Genomics Labs, University Health Network, SCV002601728.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein, SCV004183372.1

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

Description

ACMG classification criteria: PS3, PS4, PM2, PP3

#	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

From All of Us Research Program, National Institutes of Health, SCV004841640.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (6)

Description

This missense variant replaces proline with leucine at codon 81 of the VHL protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with VHL-associated tumor or have a VHL diagnosis (PMID: 17102082, 21389259, 22241717, 24134185, 33219105). This variant has been identified in 1/229958 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	108544	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Oct 20, 2024

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