ClinVar Genomic variation as it relates to human health
NM_000176.3(NR3C1):c.1088A>G (p.Asn363Ser)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000176.3(NR3C1):c.1088A>G (p.Asn363Ser)
Variation ID: 16150 Accession: VCV000016150.10
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q31.3 5: 143399752 (GRCh38) [ NCBI UCSC ] 5: 142779317 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 22, 2016 Feb 20, 2024 Jan 29, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000176.3:c.1088A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000167.1:p.Asn363Ser missense NM_001018074.1:c.1088A>G NP_001018084.1:p.Asn363Ser missense NM_001018075.1:c.1088A>G NP_001018085.1:p.Asn363Ser missense NM_001018076.2:c.1088A>G NP_001018086.1:p.Asn363Ser missense NM_001018077.1:c.1088A>G NP_001018087.1:p.Asn363Ser missense NM_001020825.2:c.1088A>G NP_001018661.1:p.Asn363Ser missense NM_001024094.2:c.1088A>G NP_001019265.1:p.Asn363Ser missense NM_001204258.2:c.1010A>G NP_001191187.1:p.Asn337Ser missense NM_001204259.2:c.833A>G NP_001191188.1:p.Asn278Ser missense NM_001204260.2:c.821A>G NP_001191189.1:p.Asn274Ser missense NM_001204261.2:c.797A>G NP_001191190.1:p.Asn266Ser missense NM_001204262.2:c.143A>G NP_001191191.1:p.Asn48Ser missense NM_001204263.2:c.98A>G NP_001191192.1:p.Asn33Ser missense NM_001204264.2:c.83A>G NP_001191193.1:p.Asn28Ser missense NM_001204265.2:c.1088A>G NP_001191194.1:p.Asn363Ser missense NM_001364180.2:c.1088A>G NP_001351109.1:p.Asn363Ser missense NM_001364181.2:c.1088A>G NP_001351110.1:p.Asn363Ser missense NM_001364182.1:c.1088A>G NP_001351111.1:p.Asn363Ser missense NM_001364183.2:c.1088A>G NP_001351112.1:p.Asn363Ser missense NM_001364184.2:c.1088A>G NP_001351113.1:p.Asn363Ser missense NM_001364185.1:c.1088A>G NP_001351114.1:p.Asn363Ser missense NC_000005.10:g.143399752T>C NC_000005.9:g.142779317T>C NG_009062.1:g.40761A>G P04150:p.Asn363Ser - Protein change
- N363S, N337S, N48S, N266S, N278S, N28S, N33S, N274S
- Other names
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- Canonical SPDI
- NC_000005.10:143399751:T:C
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00619 (C)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00619
1000 Genomes Project 30x 0.00734
Trans-Omics for Precision Medicine (TOPMed) 0.01800
The Genome Aggregation Database (gnomAD), exomes 0.01966
The Genome Aggregation Database (gnomAD) 0.01969
Exome Aggregation Consortium (ExAC) 0.02076
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.02199
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NR3C1 | - | - |
GRCh38 GRCh37 |
185 | 216 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign (1) |
no assertion criteria provided
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Aug 1, 2007 | RCV000017532.3 | |
Likely benign (1) |
criteria provided, single submitter
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Mar 6, 2018 | RCV000345541.5 | |
Benign (1) |
criteria provided, single submitter
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Jan 29, 2024 | RCV002054445.5 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely benign
(Mar 06, 2018)
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criteria provided, single submitter
Method: clinical testing
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Glucocorticoid resistance
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000453458.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
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Benign
(Jan 29, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002410416.3
First in ClinVar: Apr 08, 2022 Last updated: Feb 20, 2024 |
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Benign
(Aug 01, 2007)
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no assertion criteria provided
Method: literature only
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GLUCOCORTICOID RECEPTOR POLYMORPHISM
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000037804.2
First in ClinVar: Apr 04, 2013 Last updated: Aug 22, 2016 |
Comment on evidence:
Koper et al. (1997) identified a polymorphism, located at nucleotide position 1220 (AAT to AGT), that results in an asparagine-to-serine change in codon 363 (N363S) … (more)
Koper et al. (1997) identified a polymorphism, located at nucleotide position 1220 (AAT to AGT), that results in an asparagine-to-serine change in codon 363 (N363S) of the NR3C1 protein. Huizenga et al. (1998) investigated whether this polymorphism is associated with altered sensitivity to glucocorticoids. In a group of 216 elderly persons, they identified 13 heterozygotes for the N363S polymorphism by PCR/SSCP analysis. Thus, they found the polymorphism in 6.0% of the studied population. Huizenga et al. (1998) concluded that individuals carrying this polymorphism were clinically healthy, but had a higher sensitivity to exogenously administered glucocorticoids, with respect to both cortisol suppression and insulin response. Huizenga et al. (1998) speculated that life-long exposure to the mutated allele may be accompanied by an increased body mass index and a lowered bone mineral density in the lumbar spine with no effect on blood pressure. Dobson et al. (2001) investigated the association between the 363S allele and risk factors for coronary heart disease and diabetes mellitus in a population of European origin living in the northeast of the United Kingdom. Blood samples from 135 males and 240 females were characterized for 363 allele status. The overall frequency of the 363S allele was 3.0%; 23 heterozygotes (7 males and 16 females) but no 363S homozygotes were identified. These data showed a significant association of the 363S allele with increased waist-to-hip ratio in males but not in females. This allele was not associated with blood pressure, body mass index, serum cholesterol, triglycerides, low-density lipoprotein and high-density lipoprotein cholesterol levels, or glucose tolerance status. The authors concluded that this GR polymorphism may contribute to central obesity in men. Russcher et al. (2005) examined the effects of the N363S polymorphism on glucocorticoid sensitivity at the level of gene expression in functional assays. The N363S polymorphism, associated with increased glucocorticoid sensitivity, resulted in a significantly increased transactivating capacity, both in vitro and ex vivo. The N363S polymorphism did not seem to influence the transrepressing capacity of the glucocorticoid receptor. In a population of 295 South Asians living in the United Kingdom consisting of 35% people of Indian origin, 42% of Pakistani origin, and 19% Bangladeshi origin, Syed et al. (2004) detected a prevalence of 0.3% of the 363S allele (2 heterozygous subjects). Both subjects had raised body mass index and central obesity. The authors concluded that given its prevalence, the N363S polymorphism is unlikely to be an important factor in obesity and/or dysmetabolic traits in people of South Asian origin living in the United Kingdom. Majnik et al. (2006) found that the carrier frequency of the N363S variant in patients with bilateral adrenal incidentalomas was markedly and significantly higher than that in control subjects (20.5 vs 7.8%, P less than 0.05), but not in those with unilateral adrenal incidentalomas (7.1%) or in patients with type 2 diabetes (13.0%). Jewell and Cidlowski (2007) studied the biologic relevancy of the N363S variant on GCCR function. Functional assays with reporter gene systems and homologous downregulation revealed only minor differences between the wildtype human GCCR and N363S receptors in both transiently and stably expressing cell lines. However, examination of the 2 receptors by human gene microarray analysis revealed a unique gene expression profile for N363S. Jewell and Cidlowski (2007) noted that several of the regulated genes supported a potential role for the N363S polymorphism in human diseases. (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Molecular evidence for a link between the N363S glucocorticoid receptor polymorphism and altered gene expression. | Jewell CM | The Journal of clinical endocrinology and metabolism | 2007 | PMID: 17535992 |
Overrepresentation of the N363S variant of the glucocorticoid receptor gene in patients with bilateral adrenal incidentalomas. | Majnik J | The Journal of clinical endocrinology and metabolism | 2006 | PMID: 16636127 |
Two polymorphisms in the glucocorticoid receptor gene directly affect glucocorticoid-regulated gene expression. | Russcher H | The Journal of clinical endocrinology and metabolism | 2005 | PMID: 16030164 |
Low prevalence of the N363S polymorphism of the glucocorticoid receptor in South Asians living in the United Kingdom. | Syed AA | The Journal of clinical endocrinology and metabolism | 2004 | PMID: 14715855 |
The N363S polymorphism of the glucocorticoid receptor: potential contribution to central obesity in men and lack of association with other risk factors for coronary heart disease and diabetes mellitus. | Dobson MG | The Journal of clinical endocrinology and metabolism | 2001 | PMID: 11344238 |
A polymorphism in the glucocorticoid receptor gene may be associated with and increased sensitivity to glucocorticoids in vivo. | Huizenga NA | The Journal of clinical endocrinology and metabolism | 1998 | PMID: 9435432 |
Lack of association between five polymorphisms in the human glucocorticoid receptor gene and glucocorticoid resistance. | Koper JW | Human genetics | 1997 | PMID: 9150737 |
Text-mined citations for rs56149945 ...
HelpRecord last updated Feb 28, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.