NM_000551.4(VHL):c.414A>G (p.Pro138=) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Nov 4, 2018
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:: RCV000469600.10

Allele description [Variation Report for NM_000551.4(VHL):c.414A>G (p.Pro138=)]

NM_000551.4(VHL):c.414A>G (p.Pro138=)

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_000551.4(VHL):c.414A>G (p.Pro138=)

Other names:

P138P

HGVS:

NC_000003.12:g.10146587A>G
NG_008212.3:g.9953A>G
NG_046756.1:g.4349A>G
NM_000551.4:c.414A>GMANE SELECT
NM_001354723.2:c.*18-3200A>G
NM_198156.3:c.341-3200A>G
NP_000542.1:p.Pro138=
NP_000542.1:p.Pro138=
LRG_322t1:c.414A>G
LRG_322:g.9953A>G
LRG_322p1:p.Pro138=
NC_000003.11:g.10188271A>G
NM_000551.3:c.414A>G
p.[Pro138=]

Protein change:

PRO138PRO

Links:

OMIM: 608537.0033; dbSNP: rs869025648

NCBI 1000 Genomes Browser:

rs869025648

Molecular consequence:

NM_001354723.2:c.*18-3200A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_198156.3:c.341-3200A>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000551.4:c.414A>G - synonymous variant - [Sequence Ontology: SO:0001819]

Functional consequence:

sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071]

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
SCV000553422	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Nov 4, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000553422

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Nov 4, 2018)

germline

clinical testing

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

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

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000553422.6

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

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this silent change causes an increase of the alternative VHL transcript with skipping of exon 2 in both¬†patient-derived cells and minigene assays¬†(PMID:¬†29891534). This variant has been observed to segregate with von Hippel-Lindau (VHL) syndrome-associated tumors in several families (PMID:¬†29891534). This variant has also been observed in individuals with a personal and/or family history of¬†VHL syndrome-associated tumors¬†(Invitae). This variant is also known as P138P in the literature. ClinVar contains an entry for this variant (Variation ID: 223206). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 138 of the VHL mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the VHL protein.

#	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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