NM_000551.4(VHL):c.555C>G (p.Tyr185Ter) AND multiple conditions

Clinical significance:Likely pathogenic (Last evaluated: Feb 8, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001377065.1

Allele description [Variation Report for NM_000551.4(VHL):c.555C>G (p.Tyr185Ter)]

NM_000551.4(VHL):c.555C>G (p.Tyr185Ter)

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.555C>G (p.Tyr185Ter)
HGVS:
  • NC_000003.12:g.10149878C>G
  • NG_008212.3:g.13244C>G
  • NG_046756.1:g.7640C>G
  • NM_000551.3:c.555C>G
  • NM_000551.4:c.555C>GMANE SELECT
  • NM_001354723.2:c.*109C>G
  • NM_198156.3:c.432C>G
  • NP_000542.1:p.Tyr185Ter
  • NP_000542.1:p.Tyr185Ter
  • NP_937799.1:p.Tyr144Ter
  • LRG_322t1:c.555C>G
  • LRG_322:g.13244C>G
  • LRG_322p1:p.Tyr185Ter
  • NC_000003.11:g.10191562C>G
  • p.[Tyr185*]
Protein change:
Y144*
Links:
dbSNP: rs864622109
NCBI 1000 Genomes Browser:
rs864622109
Molecular consequence:
  • NM_001354723.2:c.*109C>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000551.3:c.555C>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_000551.4:c.555C>G - nonsense - [Sequence Ontology: SO:0001587]
  • NM_198156.3:c.432C>G - nonsense - [Sequence Ontology: SO:0001587]

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
SCV001574297Invitaecriteria provided, single submitter
Likely pathogenic
(Feb 8, 2020)
germlineclinical testing

PubMed (7)
[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

Three novel germ-line VHL mutations in Hungarian von Hippel-Lindau patients, including a nonsense mutation in a fifteen-year-old boy with renal cell carcinoma.

Losonczy G, Fazakas F, Pfliegler G, Komáromi I, Balázs E, Pénzes K, Berta A.

BMC Med Genet. 2013 Jan 8;14:3. doi: 10.1186/1471-2350-14-3.

PubMed [citation]
PMID:
23298237
PMCID:
PMC3556325

Consequences of direct genetic testing for germline mutations in the clinical management of families with multiple endocrine neoplasia, type II.

Neumann HP, Eng C, Mulligan LM, Glavac D, Zäuner I, Ponder BA, Crossey PA, Maher ER, Brauch H.

JAMA. 1995 Oct 11;274(14):1149-51.

PubMed [citation]
PMID:
7563486
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV001574297.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

This sequence change results in a premature translational stop signal in the VHL gene (p.Tyr185*). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 29 amino acids of the VHL protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with von Hippel-Lindau disease (PMID: 23298237, 7987306). This variant is also known as Tyr256Ter in the literature. ClinVar contains an entry for this variant (Variation ID: 223233). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Leu188 amino acid residue in VHL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7563486, 8772572, 7987306, 23772956, 19228690). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: Oct 30, 2021

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