NM_000551.3(VHL):c.422A>G (p.Asn141Ser) AND not provided

Clinical significance:Uncertain significance (Last evaluated: Feb 16, 2017)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV000479780.1

Allele description [Variation Report for NM_000551.3(VHL):c.422A>G (p.Asn141Ser)]

NM_000551.3(VHL):c.422A>G (p.Asn141Ser)

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.422A>G (p.Asn141Ser)
HGVS:
  • NC_000003.12:g.10146595A>G
  • NG_008212.3:g.9961A>G
  • NG_046756.1:g.4357A>G
  • NM_000551.3:c.422A>G
  • NM_001354723.2:c.18-3192A>G
  • NM_198156.3:c.341-3192A>G
  • NP_000542.1:p.Asn141Ser
  • LRG_322t1:c.422A>G
  • LRG_322:g.9961A>G
  • LRG_322p1:p.Asn141Ser
  • NC_000003.11:g.10188279A>G
Protein change:
N141S
Links:
dbSNP: rs1064796570
NCBI 1000 Genomes Browser:
rs1064796570
Molecular consequence:
  • NM_001354723.2:c.18-3192A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_198156.3:c.341-3192A>G - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000551.3:c.422A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000573399GeneDxcriteria provided, single submitter
Uncertain significance
(Feb 16, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

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

Details of each submission

From GeneDx, SCV000573399.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant is denoted VHL c.422A>G at the cDNA level, p.Asn141Ser (N141S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). This variant has not, to our knowledge, been published in the literature as either a pathogenic or benign germline variant. However, it has been reported as a somatic variant in a clear cell renal carcinoma (Khaliq 2014). VHL Asn141Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. VHL Asn141Ser occurs at a position that is conserved in mammals and is located in the region involved in binding to the CCT complex, the beta-domain which interacts with the hydroxylated oxygen-dependent degradation domain of HIF-alpha subunits, and is involved in nuclear export (Yuen 2009, UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether VHL Asn141Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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

Last Updated: May 10, 2021

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