NM_000176.3(NR3C1):c.2241T>G (p.Ile747Met) AND Glucocorticoid resistance

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jun 1, 2002
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:: RCV000017534.33

Allele description [Variation Report for NM_000176.3(NR3C1):c.2241T>G (p.Ile747Met)]

NM_000176.3(NR3C1):c.2241T>G (p.Ile747Met)

Gene:

NR3C1:nuclear receptor subfamily 3 group C member 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

5q31.3

Genomic location:

Preferred name:

NM_000176.3(NR3C1):c.2241T>G (p.Ile747Met)

HGVS:

NC_000005.10:g.143281982A>C
NG_009062.1:g.158531T>G
NM_000176.3:c.2241T>GMANE SELECT
NM_001018074.1:c.2241T>G
NM_001018075.1:c.2241T>G
NM_001018076.2:c.2241T>G
NM_001018077.1:c.2241T>G
NM_001020825.2:c.2181+586T>G
NM_001024094.2:c.2244T>G
NM_001204258.2:c.2163T>G
NM_001204259.2:c.1986T>G
NM_001204260.2:c.1974T>G
NM_001204261.2:c.1950T>G
NM_001204262.2:c.1296T>G
NM_001204263.2:c.1251T>G
NM_001204264.2:c.1236T>G
NM_001364180.2:c.2241T>G
NM_001364181.2:c.2241T>G
NM_001364182.1:c.2241T>G
NM_001364183.2:c.2244T>G
NM_001364184.2:c.2244T>G
NM_001364185.1:c.2244T>G
NP_000167.1:p.Ile747Met
NP_001018084.1:p.Ile747Met
NP_001018085.1:p.Ile747Met
NP_001018086.1:p.Ile747Met
NP_001018087.1:p.Ile747Met
NP_001019265.1:p.Ile748Met
NP_001191187.1:p.Ile721Met
NP_001191188.1:p.Ile662Met
NP_001191189.1:p.Ile658Met
NP_001191190.1:p.Ile650Met
NP_001191191.1:p.Ile432Met
NP_001191192.1:p.Ile417Met
NP_001191193.1:p.Ile412Met
NP_001351109.1:p.Ile747Met
NP_001351110.1:p.Ile747Met
NP_001351111.1:p.Ile747Met
NP_001351112.1:p.Ile748Met
NP_001351113.1:p.Ile748Met
NP_001351114.1:p.Ile748Met
NC_000005.9:g.142661547A>C
NR_157096.2:n.1164T>G
P04150:p.Ile747Met

Protein change:

I412M; ILE747MET

Links:

UniProtKB: P04150#VAR_015633; OMIM: 138040.0009; dbSNP: rs104893910

NCBI 1000 Genomes Browser:

rs104893910

Molecular consequence:

NM_001020825.2:c.2181+586T>G - intron variant - [Sequence Ontology: SO:0001627]
NM_000176.3:c.2241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018074.1:c.2241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018075.1:c.2241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018076.2:c.2241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001018077.1:c.2241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001024094.2:c.2244T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204258.2:c.2163T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204259.2:c.1986T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204260.2:c.1974T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204261.2:c.1950T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204262.2:c.1296T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204263.2:c.1251T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001204264.2:c.1236T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001364180.2:c.2241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001364181.2:c.2241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001364182.1:c.2241T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001364183.2:c.2244T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001364184.2:c.2244T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001364185.1:c.2244T>G - missense variant - [Sequence Ontology: SO:0001583]
NR_157096.2:n.1164T>G - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Glucocorticoid resistance
Synonyms:: Glucocorticoid resistance, generalized; Gccr deficiency; Glucocorticoid receptor deficiency; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0014421; MedGen: C1841972; Orphanet: 786; OMIM: 615962

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Saccharomyces cerevisiae S288C chromosome I, complete sequence
Saccharomyces cerevisiae S288C chromosome I, complete sequence
gi|330443391|ref|NC_001133.9||gnl|A F_000146045.2|I

Nucleotide
yw89c09.s1 Soares_placenta_8to9weeks_2NbHP8to9W Homo sapiens cDNA clone IMAGE:25...
yw89c09.s1 Soares_placenta_8to9weeks_2NbHP8to9W Homo sapiens cDNA clone IMAGE:259408 3', mRNA sequence
gi|1148048|gnl|dbEST|430903|gb|N295

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000037806	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2002)	germline	literature only	Vottero, A., Kino, T., Combe, H., Lecomte, P., Chrousos, G. P. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J. Clin. Endocr. Metab. 87: 2658-2667, 2002.

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000037806

OMIM

no assertion criteria provided

Pathogenic
(Jun 1, 2002)

germline

literature only

Vottero, A., Kino, T., Combe, H., Lecomte, P., Chrousos, G. P. A novel, C-terminal dominant negative mutation of the GR causes familial glucocorticoid resistance through abnormal interactions with p160 steroid receptor coactivators. J. Clin. Endocr. Metab. 87: 2658-2667, 2002.

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Details of each submission

From OMIM, SCV000037806.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	not provided

Description

Vottero et al. (2002) reported a French kindred with familial glucocorticoid resistance (GCCR; 615962) in which affected members had a heterozygous T-to-G transversion at nucleotide 2373 of exon 9-alpha of the GCCR gene, resulting in an ile747-to-met (I747M) substitution. This mutation was located close to helix 12, at the C terminus of the ligand-binding domain, which has a pivotal role in the formation of activation function (AF)-2, a subdomain that interacts with p160 coactivators. The affinity of the mutant GCCR for dexamethasone was decreased by about 2-fold, and its transcriptional activity on the glucocorticoid-responsive mouse mammary tumor virus promoter was compromised by 20- to 30-fold. In addition, the mutant GCCR functioned as a dominant-negative inhibitor of wildtype receptor-induced transactivation. The mutant GR through its intact AF-1 domain bound to a p160 coactivator, but failed to do so through its AF-2 domain. Overexpression of a p160 coactivator restored the transcriptional activity and reversed the negative transdominant activity of the mutant GCCR. The authors concluded that the mutant receptor has an ineffective AF-2 domain, which leads to an abnormal interaction with p160 coactivators and a distinct nuclear distribution of both.

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

Last Updated: Mar 26, 2023

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