NM_000551.4(VHL):c.524dup (p.Tyr175Ter) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: May 13, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003054800.3

Allele description [Variation Report for NM_000551.4(VHL):c.524dup (p.Tyr175Ter)]

NM_000551.4(VHL):c.524dup (p.Tyr175Ter)

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:

Duplication

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.524dup (p.Tyr175Ter)

HGVS:

NC_000003.12:g.10149847dup
NG_008212.3:g.13213dup
NG_046756.1:g.7609dup
NM_000551.4:c.524dupMANE SELECT
NM_001354723.2:c.*78dup
NM_198156.3:c.401dup
NP_000542.1:p.Tyr175Ter
NP_000542.1:p.Tyr175Terfs
NP_937799.1:p.Tyr134Ter
LRG_322t1:c.524dup
LRG_322:g.13213dup
LRG_322p1:p.Tyr175Terfs
NC_000003.11:g.10191530_10191531insA
NC_000003.11:g.10191531dup
NM_000551.3:c.524dup
NR_176335.1:n.853dup

Protein change:

Y134*

Molecular consequence:

NM_001354723.2:c.*78dup - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000551.4:c.524dup - nonsense - [Sequence Ontology: SO:0001587]
NM_198156.3:c.401dup - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Chuvash polycythemia
Synonyms:: POLYCYTHEMIA, VHL-DEPENDENT; Erythrocytosis, familial, 2
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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003337147	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (May 13, 2022)	germline	clinical testing	PubMed (13) [See all records that cite these PMIDs] 12202531, 25867206, 7563486, 7987306, 8707293, 8772572, 10567493, 11309459, 11331612, 16452184, 18567581, 23772956, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003337147

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(May 13, 2022)

germline

clinical testing

PubMed (13)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

Characterization of endolymphatic sac tumors and von Hippel-Lindau disease in the International Endolymphatic Sac Tumor Registry.

Bausch B, Wellner U, Peyre M, Boedeker CC, Hes FJ, Anglani M, de Campos JM, Kanno H, Maher ER, Krauss T, Sansó G, Barontini M, Letizia C, Hader C, Schiavi F, Zanoletti E, Suárez C, Offergeld C, Malinoc A, Zschiedrich S, Glasker S, Bobin S, et al.

Head Neck. 2016 Apr;38 Suppl 1:E673-9. doi: 10.1002/hed.24067. Epub 2015 Jul 14.

PubMed [citation]

PMID:: 25867206

See all PubMed Citations (13)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003337147.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This sequence change creates a premature translational stop signal (p.Tyr175*) in the VHL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 39 amino acid(s) of the VHL protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of von Hippel-Lindau syndrome (PMID: 12202531, 25867206). This variant disrupts a region of the VHL protein in which other variant(s) (p.Ser183*) have been determined to be pathogenic (PMID: 7563486, 7987306, 8707293, 8772572, 10567493, 11309459, 11331612, 16452184, 18567581, 23772956; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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