NM_000551.4(VHL):c.256C>G (p.Pro86Ala) AND Von Hippel-Lindau syndrome

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: Jan 29, 2016
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:: RCV000079208.14

Allele description [Variation Report for NM_000551.4(VHL):c.256C>G (p.Pro86Ala)]

NM_000551.4(VHL):c.256C>G (p.Pro86Ala)

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.256C>G (p.Pro86Ala)

HGVS:

NC_000003.12:g.10142103C>G
NG_008212.3:g.5469C>G
NM_000551.4:c.256C>GMANE SELECT
NM_001354723.2:c.256C>G
NM_198156.3:c.256C>G
NP_000542.1:p.Pro86Ala
NP_001341652.1:p.Pro86Ala
NP_937799.1:p.Pro86Ala
LRG_322t1:c.256C>G
LRG_322:g.5469C>G
LRG_322p1:p.Pro86Ala
NC_000003.11:g.10183787C>G
NM_000551.3:c.256C>G
P40337:p.Pro86Ala
p.[Pro86Ala]

Protein change:

P86A

Links:

UniProtKB: P40337#VAR_005693; dbSNP: rs398123481

NCBI 1000 Genomes Browser:

rs398123481

Molecular consequence:

NM_000551.4:c.256C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001354723.2:c.256C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.256C>G - 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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gi|2206727632|ref|XP_046946213.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000264683	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	no assertion criteria provided	Likely pathogenic (Feb 26, 2016)	germline	clinical testing
SCV000697489	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Jan 29, 2016)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 19304954, 22105611, 8956040, 19996202, 18836774, 9681856, 11257211, 17102082, 22825683, 7728151 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000264683

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

no assertion criteria provided

Likely pathogenic
(Feb 26, 2016)

germline

clinical testing

SCV000697489

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Jan 29, 2016)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Zebrafish mutants in the von Hippel-Lindau tumor suppressor display a hypoxic response and recapitulate key aspects of Chuvash polycythemia.

van Rooijen E, Voest EE, Logister I, Korving J, Schwerte T, Schulte-Merker S, Giles RH, van Eeden FJ.

Blood. 2009 Jun 18;113(25):6449-60. doi: 10.1182/blood-2008-07-167890. Epub 2009 Mar 20.

PubMed [citation]

PMID:: 19304954

Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease.

Jonasch E, McCutcheon IE, Waguespack SG, Wen S, Davis DW, Smith LA, Tannir NM, Gombos DS, Fuller GN, Matin SF.

Ann Oncol. 2011 Dec;22(12):2661-2666. doi: 10.1093/annonc/mdr011.

PubMed [citation]

PMID:: 22105611
PMCID:: PMC4542805

See all PubMed Citations (10)

Details of each submission

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000264683.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	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	yes	not provided	not provided	not provided		3	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697489.1

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

Description

Variant summary: This c.256C>G variant affects a conserved nucleotide, resulting in amino acid change from Pro to Ala in HIFalfa domain of VHL protein. 4/4 in-silico tools predict this variant to be damaging. This variant was found in 2/102226 control chromosomes including the broad and large population from ExAC at a frequency of 0.0000196, which is lower than the maximal expected frequency of a pathogenic allele (0.0000208) in this gene. In literature, this variant has been reported in five independent patients with Von Hippel-Lindau disease or related cancers. Other missense changes at this codon are also reported in association VHL disease, namely p.P86R, p.P86L and p.P86S, suggesting that this codon is likely to be a mutational hot-spot. One clinical lab (via ClinVar) and one reputable database classify this variant as pathogenic. Taken together, this variant is currently classified as Likely Pathogenic.

#	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: Oct 8, 2024

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