NM_000551.4(VHL):c.382_388del (p.Leu129fs) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 8, 2023
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:: RCV003807263.1

Allele description [Variation Report for NM_000551.4(VHL):c.382_388del (p.Leu129fs)]

NM_000551.4(VHL):c.382_388del (p.Leu129fs)

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:

Deletion

Cytogenetic location:

3p25.3

Genomic location:

Preferred name:

NM_000551.4(VHL):c.382_388del (p.Leu129fs)

HGVS:

NC_000003.12:g.10146555_10146561del
NG_008212.3:g.9921_9927del
NG_046756.1:g.4317_4323del
NM_000551.4:c.382_388delMANE SELECT
NM_001354723.2:c.*18-3232_*18-3226del
NM_198156.3:c.341-3232_341-3226del
NP_000542.1:p.Leu129Thrfs
NP_000542.1:p.Leu129fs
LRG_322t1:c.382_388del
LRG_322:g.9921_9927del
LRG_322p1:p.Leu129Thrfs
NC_000003.11:g.10188237_10188243del
NC_000003.11:g.10188239_10188245del
NM_000551.3:c.382_388delCTTCTGG
NR_176335.1:n.711_717del

Protein change:

L129fs

Molecular consequence:

NM_000551.4:c.382_388del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001354723.2:c.*18-3232_*18-3226del - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3232_341-3226del - intron variant - [Sequence Ontology: SO:0001627]
NR_176335.1:n.711_717del - non-coding transcript variant - [Sequence Ontology: SO:0001619]

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
SCV004608590	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 8, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 8956040, 12202531, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV004608590

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 8, 2023)

germline

clinical testing

PubMed (3)
[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

Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.

Zbar B, Kishida T, Chen F, Schmidt L, Maher ER, Richards FM, Crossey PA, Webster AR, Affara NA, Ferguson-Smith MA, Brauch H, Glavac D, Neumann HP, Tisherman S, Mulvihill JJ, Gross DJ, Shuin T, Whaley J, Seizinger B, Kley N, Olschwang S, Boisson C, et al.

Hum Mutat. 1996;8(4):348-57.

PubMed [citation]

PMID:: 8956040

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

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV004608590.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change creates a premature translational stop signal (p.Leu129Thrfs*28) in the VHL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in VHL are known to be pathogenic (PMID: 8956040, 12202531). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with VHL-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: Mar 5, 2024

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