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NM_000551.4(VHL):c.614_615del (p.Arg205fs) AND Hereditary cancer-predisposing syndrome

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jun 4, 2024
Review status:
criteria provided, conflicting classifications
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000161075.2

Allele description [Variation Report for NM_000551.4(VHL):c.614_615del (p.Arg205fs)]

NM_000551.4(VHL):c.614_615del (p.Arg205fs)

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:
Microsatellite
Cytogenetic location:
3p25.3
Genomic location:
Preferred name:
NM_000551.4(VHL):c.614_615del (p.Arg205fs)
HGVS:
  • NC_000003.12:g.10149935GC[1]
  • NG_008212.3:g.13301GC[1]
  • NG_046756.1:g.7697GC[1]
  • NM_000551.4:c.614_615delMANE SELECT
  • NM_001354723.2:c.*166GC[1]
  • NM_198156.3:c.491_492del
  • NP_000542.1:p.Arg205fs
  • NP_937799.1:p.Arg164fs
  • LRG_322:g.13301GC[1]
  • NC_000003.11:g.10191619GC[1]
  • NC_000003.11:g.10191619_10191620del
  • NM_000551.3:c.614_615delGC
  • p.R205HfsX50
Protein change:
R164fs
Links:
dbSNP: rs730882030
NCBI 1000 Genomes Browser:
rs730882030
Molecular consequence:
  • NM_001354723.2:c.*166GC[1] - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
  • NM_000551.4:c.614_615del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_198156.3:c.491_492del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000211809GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Pathogenic
(May 2, 2014) 		germlineclinical testing

Citation Link,

SCV005179673Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Uncertain significance
(Jun 4, 2024) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Retinal hemangioblastoma in von Hippel-Lindau disease: a clinical and molecular study.

Dollfus H, Massin P, Taupin P, Nemeth C, Amara S, Giraud S, Béroud C, Dureau P, Gaudric A, Landais P, Richard S.

Invest Ophthalmol Vis Sci. 2002 Sep;43(9):3067-74.

PubMed [citation]
PMID:
12202531

Details of each submission

From GeneDx, SCV000211809.2

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

Description

The c.614_615delGC mutation in the VHL gene has been reported previously in association with von Hippel-Lindau syndrome using alternate nomenclature (Dollfus et al., 2002). The deletion causes a frameshift starting with codon Arginine 205, changes this amino acid to a Histidine residue and creates a premature Stop codon at position 50 of the new reading frame, denoted p.Arg205HisfsX50. This mutation is not expected to result in protein truncation or nonsense-mediated mRNA decay as the last nine amino acids are replaced with 49 incorrect amino acids. The variant is found in VHL panel(s).

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

From Ambry Genetics, SCV005179673.1

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

Description

The c.614_615delGC variant, located in coding exon 3 of the VHL gene, results from a deletion of two nucleotides at nucleotide positions 614 to 615, causing a translational frameshift with a predicted alternate stop codon (p.R205Hfs*50). This alteration occurs at the 3' terminus of theVHL gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 40 amino acids. This frameshift impacts the last 10amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. This variant was reported in an individual with features consistent with von Hippel-Lindau Syndrome (Dollfus H et al. Invest Ophthalmol Vis Sci, 2002 Sep;43:3067-74). Based on the available evidence, the clinical significance of this variant remains unclear.

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

Last Updated: Sep 29, 2024