NM_000551.3(VHL):c.578A>G (p.Asn193Ser) AND multiple conditions

Clinical significance:Uncertain significance (Last evaluated: Sep 17, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000537589.3

Allele description [Variation Report for NM_000551.3(VHL):c.578A>G (p.Asn193Ser)]

NM_000551.3(VHL):c.578A>G (p.Asn193Ser)

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.578A>G (p.Asn193Ser)
HGVS:
  • NC_000003.12:g.10149901A>G
  • NG_008212.3:g.13267A>G
  • NG_046756.1:g.7663A>G
  • NM_000551.3:c.578A>G
  • NM_001354723.2:c.*132A>G
  • NM_198156.3:c.455A>G
  • NP_000542.1:p.Asn193Ser
  • NP_937799.1:p.Asn152Ser
  • LRG_322t1:c.578A>G
  • LRG_322:g.13267A>G
  • LRG_322p1:p.Asn193Ser
  • NC_000003.11:g.10191585A>G
Protein change:
N152S
Links:
dbSNP: rs879254225
NCBI 1000 Genomes Browser:
rs879254225
Molecular consequence:
  • NM_001354723.2:c.*132A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000551.3:c.578A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_198156.3:c.455A>G - 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
SCV000626911Invitaecriteria provided, single submitter
Uncertain significance
(Sep 17, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Invitae, SCV000626911.3

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

Description

This sequence change replaces asparagine with serine at codon 193 of the VHL protein (p.Asn193Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with VHL-related disease. ClinVar contains an entry for this variant (Variation ID: 246368). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: May 10, 2021

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