NM_005154.5(USP8):c.2159C>G (p.Pro720Arg) AND Pituitary dependent hypercortisolism

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Sep 26, 2017
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

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:: RCV000149420.6

Allele description [Variation Report for NM_005154.5(USP8):c.2159C>G (p.Pro720Arg)]

NM_005154.5(USP8):c.2159C>G (p.Pro720Arg)

Gene:

USP8:ubiquitin specific peptidase 8 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

15q21.2

Genomic location:

Preferred name:

NM_005154.5(USP8):c.2159C>G (p.Pro720Arg)

HGVS:

NC_000015.10:g.50490450C>G
NG_047101.1:g.71074C>G
NM_001128610.3:c.2159C>G
NM_001283049.2:c.1841C>G
NM_005154.5:c.2159C>GMANE SELECT
NP_001122082.1:p.Pro720Arg
NP_001269978.1:p.Pro614Arg
NP_005145.3:p.Pro720Arg
NC_000015.9:g.50782647C>G
NM_005154.3:c.2159C>G
NM_005154.4:c.2159C>G
hg19.chr15:g.50782647C>G

Protein change:

P614R; PRO720ARG

Links:

OMIM: 603158.0002; dbSNP: rs672601311

NCBI 1000 Genomes Browser:

rs672601311

Molecular consequence:

NM_001128610.3:c.2159C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001283049.2:c.1841C>G - missense variant - [Sequence Ontology: SO:0001583]
NM_005154.5:c.2159C>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Pituitary dependent hypercortisolism
Synonyms:: CUSHING DISEASE, PITUITARY; Pituitary ACTH Hypersecretion; Pituitary adenoma, acth-secreting, somatic; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009050; MedGen: C0221406; Orphanet: 96253; OMIM: 219090

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000192011	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	no assertion criteria provided	Pathogenic (Nov 18, 2014)	somatic	research
SCV000605826	OMIM	no assertion criteria provided	Pathogenic (Sep 26, 2017)	somatic	literature only	PubMed (2) [See all records that cite these PMIDs] 25675982, 25942478

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000192011

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

no assertion criteria provided

Pathogenic
(Nov 18, 2014)

somatic

research

SCV000605826

OMIM

no assertion criteria provided

Pathogenic
(Sep 26, 2017)

somatic

literature only

PubMed (2)
[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	somatic	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Caucasian	somatic	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Recurrent gain-of-function USP8 mutations in Cushing's disease.

Ma ZY, Song ZJ, Chen JH, Wang YF, Li SQ, Zhou LF, Mao Y, Li YM, Hu RG, Zhang ZY, Ye HY, Shen M, Shou XF, Li ZQ, Peng H, Wang QZ, Zhou DZ, Qin XL, Ji J, Zheng J, Chen H, Wang Y, et al.

Cell Res. 2015 Mar;25(3):306-17. doi: 10.1038/cr.2015.20. Epub 2015 Feb 13.

PubMed [citation]

PMID:: 25675982
PMCID:: PMC4349249

The Gene of the Ubiquitin-Specific Protease 8 Is Frequently Mutated in Adenomas Causing Cushing's Disease.

Perez-Rivas LG, Theodoropoulou M, Ferraù F, Nusser C, Kawaguchi K, Stratakis CA, Faucz FR, Wildemberg LE, Assié G, Beschorner R, Dimopoulou C, Buchfelder M, Popovic V, Berr CM, Tóth M, Ardisasmita AI, Honegger J, Bertherat J, Gadelha MR, Beuschlein F, Stalla G, Komada M, et al.

J Clin Endocrinol Metab. 2015 Jul;100(7):E997-1004. doi: 10.1210/jc.2015-1453. Epub 2015 May 5.

PubMed [citation]

PMID:: 25942478
PMCID:: PMC4490309

Details of each submission

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV000192011.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Caucasian	1	not provided	not provided	research	not provided

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

From OMIM, SCV000605826.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In a screen of 108 ACTH-secreting pituitary adenomas (PITA4; 219090), Ma et al. (2015) identified 17 different heterozygous somatic mutations in the USP8 gene, including a c.2159C-G somatic mutation, resulting in a pro720-to-arg (P720R), as 1 of 3 recurrent mutations accounting for over 77% of the USP8-mutated tumors. None of the 17 mutations were found in the dbSNP (build 138) or 1000 Genomes Project databases. Functional studies in 293T cells showed that the mutant failed to bind 14-3-3 protein, and in HeLa cells, the mutant showed reduced EGFR ubiquitination compared to wildtype, indicating that the mutation results in a gain of function.

By Sanger sequencing in 134 corticotroph adenomas from patients with Cushing disease, Perez-Rivas et al. (2015) identified USP8 mutations in 48 tumors, including the P720R mutation in 2 (4.1%).

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

Last Updated: Jun 23, 2024

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