NM_000551.4(VHL):c.524A>G (p.Tyr175Cys) AND multiple conditions

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 10, 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:: RCV000533687.9

Allele description [Variation Report for NM_000551.4(VHL):c.524A>G (p.Tyr175Cys)]

NM_000551.4(VHL):c.524A>G (p.Tyr175Cys)

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.524A>G (p.Tyr175Cys)

HGVS:

NC_000003.12:g.10149847A>G
NG_008212.3:g.13213A>G
NG_046756.1:g.7609A>G
NM_000551.4:c.524A>GMANE SELECT
NM_001354723.2:c.*78A>G
NM_198156.3:c.401A>G
NP_000542.1:p.Tyr175Cys
NP_000542.1:p.Tyr175Cys
NP_937799.1:p.Tyr134Cys
LRG_322t1:c.524A>G
LRG_322:g.13213A>G
LRG_322p1:p.Tyr175Cys
NC_000003.11:g.10191531A>G
NM_000551.3:c.524A>G

Protein change:

Y134C

Links:

dbSNP: rs193922613

NCBI 1000 Genomes Browser:

rs193922613

Molecular consequence:

NM_001354723.2:c.*78A>G - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_000551.4:c.524A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_198156.3:c.401A>G - missense variant - [Sequence Ontology: SO:0001583]

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

Recent activity

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Hepacivirus hominis gene for glycoprotein, partial cds, clone: NDM286I-01
Hepacivirus hominis gene for glycoprotein, partial cds, clone: NDM286I-01
gi|54650365|dbj|AB182840.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000626909	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 10, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 23859443, 30105105, 14722919, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000626909

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 10, 2023)

germline

clinical testing

PubMed (4)
[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

Molecular study of congenital erythrocytosis in 70 unrelated patients revealed a potential causal mutation in less than half of the cases (Where is/are the missing gene(s)?).

Bento C, Almeida H, Maia TM, Relvas L, Oliveira AC, Rossi C, Girodon F, Fernandez-Lago C, Aguado-Diaz A, Fraga C, Costa RM, Araújo AL, Silva J, Vitória H, Miguel N, Silveira MP, Martin-Nuñez G, Ribeiro ML.

Eur J Haematol. 2013 Oct;91(4):361-8. doi: 10.1111/ejh.12170. Epub 2013 Aug 20.

PubMed [citation]

PMID:: 23859443

Bilateral Pheochromocytomas in a Patient with Y175C Von Hippel-Lindau Mutation.

Astapova O, Biswas A, DiMauro A, Moalem J, Hammes SR.

Case Rep Endocrinol. 2018;2018:8967159. doi: 10.1155/2018/8967159.

PubMed [citation]

PMID:: 30105105
PMCID:: PMC6076969

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000626909.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 175 of the VHL protein (p.Tyr175Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with a personal and/or family history of VHL-associated tumors, erythrocytosis and von Hippel-Lindau (VHL) syndrome (PMID: 14722919, 23859443, 30105105; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 36905). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt VHL protein function. This variant disrupts the p.Tyr175 amino acid residue in VHL. Other variant(s) that disrupt this residue have been observed in individuals with VHL-related conditions (PMID: 14722919), which suggests that this may be a clinically significant amino acid residue. 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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