ClinVar Genomic variation as it relates to human health
NM_003977.4(AIP):c.26G>A (p.Arg9Gln)
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.
Uncertain significance(6); Likely benign(2)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003977.4(AIP):c.26G>A (p.Arg9Gln)
Variation ID: 485052 Accession: VCV000485052.36
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.2 11: 67250655 (GRCh37) [ NCBI UCSC ] 11: 67483184 (GRCh38) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Nov 3, 2018 May 12, 2024 Jan 31, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_003977.4:c.26G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003968.3:p.Arg9Gln missense NM_001302960.2:c.26G>A NP_001289889.1:p.Arg9Gln missense NC_000011.10:g.67483184G>A NC_000011.9:g.67250655G>A NG_008969.1:g.5151G>A LRG_460:g.5151G>A LRG_460t1:c.26G>A - Protein change
- R9Q
- Other names
- -
- Canonical SPDI
- NC_000011.10:67483183:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
-
-
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.
-
0.00020 (A)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00016
1000 Genomes Project 0.00020
Exome Aggregation Consortium (ExAC) 0.00021
The Genome Aggregation Database (gnomAD), exomes 0.00026
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00031
The Genome Aggregation Database (gnomAD) 0.00037
Trans-Omics for Precision Medicine (TOPMed) 0.00045
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 | ||
---|---|---|---|---|---|---|
HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
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. |
|||
AIP | - | - |
GRCh38 GRCh37 |
817 | 1000 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
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
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
---|---|---|---|---|
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
|
Nov 23, 2021 | RCV000561910.9 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Jan 31, 2024 | RCV001054806.27 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Oct 31, 2018 | RCV000765005.3 | |
Uncertain significance (1) |
criteria provided, single submitter
|
Jan 19, 2023 | RCV001764674.3 |
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
Help
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
Help
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. |
|
---|---|---|---|---|---|
Likely benign
(Feb 18, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000672425.5
First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024 |
Comment:
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more)
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
|
|
Uncertain significance
(May 01, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001747603.15
First in ClinVar: Jul 10, 2021 Last updated: May 12, 2024 |
Number of individuals with the variant: 1
|
|
Uncertain significance
(Nov 03, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002009993.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
|
Uncertain significance
(Nov 23, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002535435.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The AIP c.26G>A (p.R9Q) variant has been reported in heterozygosity in at least three individuals with pituitary adenomas and one with primary hyperparathyroidism (PMID: 22319033, … (more)
The AIP c.26G>A (p.R9Q) variant has been reported in heterozygosity in at least three individuals with pituitary adenomas and one with primary hyperparathyroidism (PMID: 22319033, 23038625, 29036195). Functional studies have shown that this variant demonstrates small but statistically significant decreases in protein stability and regulation of cellular proliferation, as well as effecting interactions with cAMP and GH (PMID: 28255869). In silico predictions of the variant's effect on protein function are inconclusive. It was observed in 28/35436 chromosomes of the Latino subpopulation, with no homozygotes, in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). This variant has been reported in ClinVar (Variation ID 485052). The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)
|
|
|
Uncertain significance
(Dec 21, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV002601483.2
First in ClinVar: Nov 19, 2022 Last updated: Mar 04, 2023 |
Comment:
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with pituitary adenomas and/or multiple neuroendocrine neoplasia in published … (more)
In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with pituitary adenomas and/or multiple neuroendocrine neoplasia in published literature (Cazabat et al., 2012; Oriola et al., 2013; Lecoq et al., 2016; Pardi et al., 2017; Martinez de LaPiscina et al., 2021); Published functional studies demonstrate partially reduced protein stability, cellular proliferation and cAMP-directed expression (Formosa et al., 2017); This variant is associated with the following publications: (PMID: 22319033, 29036195, 23038625, 30941100, 26792934, 34313605, 25614825, 29308445, 28255869) (less)
|
|
Uncertain significance
(Jan 19, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Somatotroph adenoma
Affected status: unknown
Allele origin:
germline
|
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Accession: SCV003842999.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
The AIP c.26G>A (p.Arg9Gln) missense change has a maximum subpopulation frequency of 0.079% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been reported in individuals with … (more)
The AIP c.26G>A (p.Arg9Gln) missense change has a maximum subpopulation frequency of 0.079% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). This variant has been reported in individuals with prolactin-secreting pituitary adenomas and hormonal dysfunction (PMID: 22319033, 34313605), an individual with a pituitary macroadenoma of unknown type (PMID: 23038625), and an individual with multiglandular familial primary hyperparathyroidism and a mixed prolactin- and GH-secreting pituitary adenoma (PMID: 29036195). The in silico tool REVEL predicts a benign effect on protein function, and in vitro functional studies demonstrated that this variant impacts the cAMP inhibitory ability of the wild-type AIP protein and may decrease the half-life of the protein (PMID: 28255869). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.? (less)
|
|
Uncertain significance
(Oct 31, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Acroleukopathy, symmetric
Somatotroph adenoma Pituitary dependent hypercortisolism
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV000896188.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
|
|
Likely benign
(Jan 31, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV001219159.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
unknown
|
Department of Pathology and Laboratory Medicine, Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001550414.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The AIP p.Arg9Gln variant was identified in dbSNP (ID: rs139459091) as “With Uncertain significance allele”, ClinVar (Uncertain Significance, Ambry Genetics), the LOVD 3.0 database (as … (more)
The AIP p.Arg9Gln variant was identified in dbSNP (ID: rs139459091) as “With Uncertain significance allele”, ClinVar (Uncertain Significance, Ambry Genetics), the LOVD 3.0 database (as Likely Pathogenic), the 1000 Genomes Project in 1 of 5000 chromosomes (frequency: 0.0002) and the NHLBI GO Exome Sequencing Project in 4 of 8586 European American and 0 of 4400 African American alleles. The variant was identified in gnomAD (Feb 27, 2017) control databases in 69 of 282814 chromosomes at a frequency of 0.000244. It was observed in the following populations: Latino in 28 of 35436 chromosomes (freq: 0.00079), Other in 5 of 7226 chromosomes (freq: 0.000692), European (non-Finnish) in 34 of 129136 chromosomes (freq: 0.000263), Ashkenazi Jewish in 1 of 10368 chromosomes (freq: 0.000096) and African in 1 of 24962 chromosomes (freq: 0.00004); it was not observed in the East Asian, European (Finnish) and South Asian populations. The AIP p.Arg9Gln variant was identified in a 21 year-old female with Acromegaly and a pituitary macroadenoma, but was not identified in the controls (Oriola_2012_PMID: 23038625). This patient presented with complete resistance to somatostatin analogues and had no family history of pituitary adenomas or other endocrine tumors. Similarly, the variant was identified in a 14 year-old female with PRL-secreting pituitary macroadenoma (diameter between 10 and 29 mm) originally presenting with primary amenorrhea and a 39 year-old female with ACTH-secreting microadenoma sized (diameter less than 10 mm) originally presenting with Cushing syndrome (Cazabat_2012_PMID: 22319033). Both of these patients had no family history of pituitary adenomas. In a study by Pardi et al., the p.Arg9Gln variant was identified in two Italian patients with sporadic cases of multiple endocrine neoplasia type 1 (no family history of multiple endocrine neoplasia–related manifestations), but was not identified in healthy controls (Pardi_2017_PMID: 29036195). The p.Arg9 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD and BLOSUM) do not suggest a high likelihood of impact to the protein. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE and GeneSplicer) do not predict a difference in splicing. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. (less)
|
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 |
---|---|---|---|---|
Mutational and large deletion study of genes implicated in hereditary forms of primary hyperparathyroidism and correlation with clinical features. | Pardi E | PloS one | 2017 | PMID: 29036195 |
Aryl Hydrocarbon Receptor-Interacting Protein (AIP) N-Terminus Gene Mutations Identified in Pituitary Adenoma Patients Alter Protein Stability and Function. | Formosa R | Hormones & cancer | 2017 | PMID: 28255869 |
Very low frequency of germline GPR101 genetic variation and no biallelic defects with AIP in a large cohort of patients with sporadic pituitary adenomas. | Lecoq AL | European journal of endocrinology | 2016 | PMID: 26792934 |
Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues. | Oriola J | European journal of endocrinology | 2012 | PMID: 23038625 |
Germline AIP mutations in apparently sporadic pituitary adenomas: prevalence in a prospective single-center cohort of 443 patients. | Cazabat L | The Journal of clinical endocrinology and metabolism | 2012 | PMID: 22319033 |
Text-mined citations for rs139459091 ...
HelpRecord last updated May 12, 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.