NM_000551.3(VHL):c.345C>A (p.His115Gln) AND Von Hippel-Lindau syndrome

Clinical significance:Pathogenic (Last evaluated: Feb 5, 2016)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000588324.1

Allele description [Variation Report for NM_000551.3(VHL):c.345C>A (p.His115Gln)]

NM_000551.3(VHL):c.345C>A (p.His115Gln)

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_000551.3(VHL):c.345C>A (p.His115Gln)
HGVS:
  • NC_000003.12:g.10146518C>A
  • NG_008212.3:g.9884C>A
  • NG_046756.1:g.4280C>A
  • NM_000551.3:c.345C>A
  • NM_001354723.2:c.18-3269C>A
  • NM_198156.3:c.341-3269C>A
  • NP_000542.1:p.His115Gln
  • LRG_322t1:c.345C>A
  • LRG_322:g.9884C>A
  • LRG_322p1:p.His115Gln
  • NC_000003.11:g.10188202C>A
Protein change:
H115Q
Links:
dbSNP: rs864622646
NCBI 1000 Genomes Browser:
rs864622646
Molecular consequence:
  • NM_001354723.2:c.18-3269C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_198156.3:c.341-3269C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000551.3:c.345C>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000697502Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Pathogenic
(Feb 5, 2016)
germlineclinical testing

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

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Summary from all submissions

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

Citations

PubMed

GESPA: classifying nsSNPs to predict disease association.

Khurana JK, Reeder JE, Shrimpton AE, Thakar J.

BMC Bioinformatics. 2015 Jul 25;16:228. doi: 10.1186/s12859-015-0673-2.

PubMed [citation]
PMID:
26206375
PMCID:
PMC4513380

Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel-Lindau (VHL) disease.

Hwang S, Ku CR, Lee JI, Hur KY, Lee MS, Lee CH, Koo KY, Lee JS, Rhee Y.

J Hum Genet. 2014 Sep;59(9):488-93. doi: 10.1038/jhg.2014.61. Epub 2014 Jul 31.

PubMed [citation]
PMID:
25078357
See all PubMed Citations (8)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000697502.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

Variant summary: This c.345C>A affects a non-conserved nucleotide, resulting in amino acid change from His to Gln. 2/3 in-silico tools predict this variant to be damaging. The residue p.His115 is reported to be critical for interaction with HIF, thus this missense change is unlikely to be tolerated. By a structural/functional assay, interaction energy of residue was ~1.5 kcal/mol weaker than that with histidine in the wild type (Domene_2012), thus proving that the variant leads to functional impairment. This variant was not found in approximately 121600 control chromosomes, including the broad and large populations from ExAC. In literature, the p.His115Gln has been reported as a pathogenic variant found in >6 independent VHL patients/families, including somatic occurrences. At least one database calls this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic.

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

Last Updated: Jun 14, 2021

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