NM_000551.4(VHL):c.160A>T (p.Met54Leu) AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Apr 17, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001046725.2

Allele description [Variation Report for NM_000551.4(VHL):c.160A>T (p.Met54Leu)]

NM_000551.4(VHL):c.160A>T (p.Met54Leu)

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.160A>T (p.Met54Leu)
HGVS:
  • NC_000003.12:g.10142007A>T
  • NG_008212.3:g.5373A>T
  • NM_000551.4:c.160A>TMANE SELECT
  • NM_001354723.2:c.160A>T
  • NM_198156.3:c.160A>T
  • NP_000542.1:p.Met54Leu
  • NP_001341652.1:p.Met54Leu
  • NP_937799.1:p.Met54Leu
  • LRG_322t1:c.160A>T
  • LRG_322:g.5373A>T
  • NC_000003.11:g.10183691A>T
  • NM_000551.3:c.160A>T
Protein change:
M54L
Molecular consequence:
  • NM_000551.4:c.160A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354723.2:c.160A>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.160A>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Erythrocytosis, familial, 2 (ECYT2)
Synonyms:
POLYCYTHEMIA, CHUVASH TYPE; POLYCYTHEMIA, VHL-DEPENDENT
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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001210639Invitaecriteria provided, single submitter
Likely pathogenic
(Apr 17, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

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

Citations

PubMed

Pulmonary arterial hypertension associated with a von Hippel-Lindau gene mutation.

Caravita S, Deboeck G, Vachiery JL, Naeije R.

J Heart Lung Transplant. 2016 Sep;35(9):1138-9. doi: 10.1016/j.healun.2016.07.002. Epub 2016 Jul 16. No abstract available.

PubMed [citation]
PMID:
27578599

Novel Homozygous Mutation of the Internal Translation Initiation Start Site of VHL is Exclusively Associated with Erythrocytosis: Indications for Distinct Functional Roles of von Hippel-Lindau Tumor Suppressor Isoforms.

Bartels M, van der Zalm MM, van Oirschot BA, Lee FS, Giles RH, Kruip MJ, Gitz-Francois JJ, Van Solinge WW, Bierings M, van Wijk R.

Hum Mutat. 2015 Nov;36(11):1039-42. doi: 10.1002/humu.22846. Epub 2015 Aug 17.

PubMed [citation]
PMID:
26224408
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001210639.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change affects the initiator methionine of the VHL mRNA at codon 54 (Met54), which is responsible for translation initiation of the VHLp19 functional isoform. However, the initiator methionine at codon 1 (Met1) responsible for translation initiation of the VHLp30 functional isoform is preserved. This variant is not present in population databases (ExAC no frequency). Disruption of the initiator Met54 codon (p.Met54Ile) has been observed to be homozygous in individuals of Moroccan origin who were affected with erythrocytosis and pulmonary arterial hypertension, and reported to segregate with erythrocytosis in a family (PMID: 26224408, 27578599). However, individuals observed to be heterozygous did not present von Hippel-Lindau (VHL) associated clinical features (PMID: 26224408), suggesting that its association with VHL is currently unclear. Experimental studies using patient's cells have shown that disruption of Met54 (p.Met54Ile) affects VHLp19 expression, but does not affect VHLp30 expression (PMID: 26224408). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: May 10, 2021

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