NM_000551.4(VHL):c.497T>C (p.Val166Ala) AND Von Hippel-Lindau syndrome

Clinical significance:Pathogenic (Last evaluated: Aug 1, 2018)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000036549.3

Allele description [Variation Report for NM_000551.4(VHL):c.497T>C (p.Val166Ala)]

NM_000551.4(VHL):c.497T>C (p.Val166Ala)

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.497T>C (p.Val166Ala)
HGVS:
  • NC_000003.12:g.10149820T>C
  • NG_008212.3:g.13186T>C
  • NG_046756.1:g.7582T>C
  • NM_000551.4:c.497T>CMANE SELECT
  • NM_001354723.2:c.*51T>C
  • NM_198156.3:c.374T>C
  • NP_000542.1:p.Val166Ala
  • NP_000542.1:p.Val166Ala
  • NP_937799.1:p.Val125Ala
  • LRG_322t1:c.497T>C
  • LRG_322:g.13186T>C
  • LRG_322p1:p.Val166Ala
  • NC_000003.11:g.10191504T>C
  • NM_000551.2:c.497T>C
  • NM_000551.3:c.497T>C
  • c.497T>C
Protein change:
V125A
Links:
dbSNP: rs397516445
NCBI 1000 Genomes Browser:
rs397516445
Molecular consequence:
  • NM_001354723.2:c.*51T>C - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000551.4:c.497T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.374T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000060204Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicinecriteria provided, single submitter
Pathogenic
(Sep 11, 2012)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000897837Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphiacriteria provided, single submitter
Pathogenic
(Aug 1, 2018)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

Frequency of Von Hippel-Lindau germline mutations in classic and non-classic Von Hippel-Lindau disease identified by DNA sequencing, Southern blot analysis and multiplex ligation-dependent probe amplification.

Hes FJ, van der Luijt RB, Janssen AL, Zewald RA, de Jong GJ, Lenders JW, Links TP, Luyten GP, Sijmons RH, Eussen HJ, Halley DJ, Lips CJ, Pearson PL, van den Ouweland AM, Majoor-Krakauer DF.

Clin Genet. 2007 Aug;72(2):122-9. Erratum in: Clin Genet. 2008 Apr;73(4):399.

PubMed [citation]
PMID:
17661816

Mutations of the VHL gene in sporadic renal cell carcinoma: definition of a risk factor for VHL patients to develop an RCC.

Gallou C, Joly D, Méjean A, Staroz F, Martin N, Tarlet G, Orfanelli MT, Bouvier R, Droz D, Chrétien Y, Maréchal JM, Richard S, Junien C, Béroud C.

Hum Mutat. 1999;13(6):464-75.

PubMed [citation]
PMID:
10408776
See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, SCV000060204.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

The Val166Ala variant has previously been reported to have occurred de novo in a n individual with clinical features of Von Hippel-Lindau syndrome and has been i dentified in one affected individual previously tested by our laboratory (Hes 20 07, LMM unpublished data). Valine (Val) at position 166 is not evolutionarily co nserved in mammals (rabbit and pika have an isoleucine at this position), howeve r, a different amino acid change at this location (Val166Phe) has also been asso ciated with the clinical features of Von Hippel-Lindau syndrome (Maher 1996). Co mputational analyses (biochemical amino acid properties, conservation, AlignGVGD , PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein, but structural evidence suggests this amino acid plays an importan t role in VHL function (Stebbins 1999). In summary, this variant is highly likel y to be pathogenic based on its de novo occurrence in a patient with sporadic di sease.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia, SCV000897837.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Dec 4, 2021

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