This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 18381572, 25184284]
ClinVar Genomic variation as it relates to human health
NM_003977.4(AIP):c.807C>T (p.Phe269=)
Germline
Classification
Help
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.
(13)
Help
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.
Conflicting classifications of pathogenicity
Uncertain significance(1); Likely benign(6)
Uncertain significance(1); Likely benign(6)
13
criteria provided, conflicting classifications
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_003977.4(AIP):c.807C>T (p.Phe269=)
Variation ID: 41209 Accession: VCV000041209.34
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 11q13.2 11: 67490807 (GRCh38) [ NCBI UCSC ] 11: 67258278 (GRCh37) [ 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 May 3, 2013 Oct 20, 2024 Aug 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_003977.4:c.807C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_003968.3:p.Phe269= synonymous NM_001302959.2:c.630C>T NP_001289888.1:p.Phe210= synonymous NM_001302960.1:c.799C>T NM_001302960.2:c.799C>T NP_001289889.1:p.Gln267Ter nonsense NC_000011.10:g.67490807C>T NC_000011.9:g.67258278C>T NG_008969.1:g.12774C>T LRG_460:g.12774C>T LRG_460t1:c.807C>T - Protein change
- Q267*
- Other names
- -
- Canonical SPDI
- NC_000011.10:67490806:C:T
-
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.
-
0.00040 (T)
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00056
Exome Aggregation Consortium (ExAC) 0.00059
Trans-Omics for Precision Medicine (TOPMed) 0.00070
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00092
1000 Genomes Project 0.00040
1000 Genomes Project 30x 0.00047
The Genome Aggregation Database (gnomAD) 0.00055
- Links
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 |
838 | 1025 | |
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 (3) |
criteria provided, conflicting classifications
|
Dec 21, 2018 | RCV000034108.11 | |
| Likely benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jun 23, 2021 | RCV000571925.6 | |
| Likely benign (7) |
criteria provided, multiple submitters, no conflicts
|
Aug 1, 2024 | RCV000951118.19 | |
|
AIP-related disorder
|
Likely benign (1) |
no assertion criteria provided
|
Aug 25, 2023 | RCV003952391.2 |
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. |
|
|---|---|---|---|---|---|
|
Uncertain significance
(Dec 21, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Somatotroph adenoma
Affected status: yes
Allele origin:
unknown
|
Baylor Genetics
Study: CSER-TexasKidsCanSeq
Accession: SCV001483039.1 First in ClinVar: Mar 07, 2021 Last updated: Mar 07, 2021 |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 18381572, … (more)
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 18381572, 25184284] (less)
|
|
|
Likely benign
(Jul 17, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV001772730.1
First in ClinVar: Aug 07, 2021 Last updated: Aug 07, 2021 |
Comment:
This variant is associated with the following publications: (PMID: 2200621, 26186299, 21753072, 17609395, 28220018, 23038625, 18381572, 25184284, 20506337, 18410548)
|
|
|
Likely benign
(Mar 20, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000672424.5
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)
|
|
|
Likely benign
(Apr 28, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Somatotroph adenoma
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000373583.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
|
|
Likely benign
(Feb 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001097483.6
First in ClinVar: Dec 17, 2019 Last updated: Feb 20, 2024 |
|
|
|
Likely benign
(Aug 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV005330177.2
First in ClinVar: Oct 08, 2024 Last updated: Oct 20, 2024 |
Comment:
AIP: BP4, BP7
Number of individuals with the variant: 1
|
|
|
Likely benign
(Jun 23, 2021)
|
criteria provided, single submitter
Method: curation
|
Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002535458.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
|
|
Likely benign
(Aug 25, 2023)
|
no assertion criteria provided
Method: clinical testing
|
AIP-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004770356.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
|
|
|
Likely benign
(-)
|
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: SCV001548583.1 First in ClinVar: Apr 13, 2021 Last updated: Apr 13, 2021 |
Comment:
The AIP p.F269F variant was identified in 5 individuals with pituitary adenoma, acromegaly, gigantism, or macroadenoma, however the variant was also identified in unaffected family … (more)
The AIP p.F269F variant was identified in 5 individuals with pituitary adenoma, acromegaly, gigantism, or macroadenoma, however the variant was also identified in unaffected family members (DeSousa_2017_PMID:28220018; Preda_2014_PMID:25184284; Oriola_2012_PMID:23038625; Igreja_2010_PMID:20506337). Functional studies reveal that individuals and in vitro models with this variant have decreased AIP mRNA expression compared to control (Igreja_2010_PMID:20506337). The variant was identified in dbSNP (ID: rs139407567), LOVD 3.0 and ClinVar (classified as uncertain significance by Ambry Genetics and as likely benign by Illumina and Invitae). The variant was identified in control databases in 154 of 280240 chromosomes at a frequency of 0.0005495 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 112 of 127076 chromosomes (freq: 0.000881), South Asian in 21 of 30602 chromosomes (freq: 0.000686), Other in 4 of 7176 chromosomes (freq: 0.000557), Latino in 10 of 35398 chromosomes (freq: 0.000283), African in 6 of 24736 chromosomes (freq: 0.000243) and European (Finnish) in 1 of 25074 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, or East Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. (less)
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001969490.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001741536.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
|
|
Uncertain significance
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001958502.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
|
|
|
not provided
(-)
|
no classification provided
Method: literature only
|
Somatotroph adenoma
Affected status: not provided
Allele origin:
unknown
|
GeneReviews
Accession: SCV000058038.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022 |
|
|
| click to load more click to collapse | |||||
Comment:
Comment:
This variant is associated with the following publications: (PMID: 2200621, 26186299, 21753072, 17609395, 28220018, 23038625, 18381572, 25184284, 20506337, 18410548)
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 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.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
AIP: BP4, BP7
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Comment:
The AIP p.F269F variant was identified in 5 individuals with pituitary adenoma, acromegaly, gigantism, or macroadenoma, however the variant was also identified in unaffected family members (DeSousa_2017_PMID:28220018; Preda_2014_PMID:25184284; Oriola_2012_PMID:23038625; Igreja_2010_PMID:20506337). Functional studies reveal that individuals and in vitro models with this variant have decreased AIP mRNA expression compared to control (Igreja_2010_PMID:20506337). The variant was identified in dbSNP (ID: rs139407567), LOVD 3.0 and ClinVar (classified as uncertain significance by Ambry Genetics and as likely benign by Illumina and Invitae). The variant was identified in control databases in 154 of 280240 chromosomes at a frequency of 0.0005495 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 112 of 127076 chromosomes (freq: 0.000881), South Asian in 21 of 30602 chromosomes (freq: 0.000686), Other in 4 of 7176 chromosomes (freq: 0.000557), Latino in 10 of 35398 chromosomes (freq: 0.000283), African in 6 of 24736 chromosomes (freq: 0.000243) and European (Finnish) in 1 of 25074 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, or East Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
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. |
Comment:
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported as disease-causing [PMID 18381572, 25184284]
Comment:
This variant is associated with the following publications: (PMID: 2200621, 26186299, 21753072, 17609395, 28220018, 23038625, 18381572, 25184284, 20506337, 18410548)
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 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.
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Comment:
AIP: BP4, BP7
Comment:
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Comment:
The AIP p.F269F variant was identified in 5 individuals with pituitary adenoma, acromegaly, gigantism, or macroadenoma, however the variant was also identified in unaffected family members (DeSousa_2017_PMID:28220018; Preda_2014_PMID:25184284; Oriola_2012_PMID:23038625; Igreja_2010_PMID:20506337). Functional studies reveal that individuals and in vitro models with this variant have decreased AIP mRNA expression compared to control (Igreja_2010_PMID:20506337). The variant was identified in dbSNP (ID: rs139407567), LOVD 3.0 and ClinVar (classified as uncertain significance by Ambry Genetics and as likely benign by Illumina and Invitae). The variant was identified in control databases in 154 of 280240 chromosomes at a frequency of 0.0005495 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 112 of 127076 chromosomes (freq: 0.000881), South Asian in 21 of 30602 chromosomes (freq: 0.000686), Other in 4 of 7176 chromosomes (freq: 0.000557), Latino in 10 of 35398 chromosomes (freq: 0.000283), African in 6 of 24736 chromosomes (freq: 0.000243) and European (Finnish) in 1 of 25074 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish, or East Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| AIP Familial Isolated Pituitary Adenomas. | Adam MP | - | 2020 | PMID: 22720333 |
| Germline variants in familial pituitary tumour syndrome genes are common in young patients and families with additional endocrine tumours. | De Sousa SMC | European journal of endocrinology | 2017 | PMID: 28220018 |
| Landscape of Familial Isolated and Young-Onset Pituitary Adenomas: Prospective Diagnosis in AIP Mutation Carriers. | Hernández-Ramírez LC | The Journal of clinical endocrinology and metabolism | 2015 | PMID: 26186299 |
| Low rate of germline AIP mutations in patients with apparently sporadic pituitary adenomas before the age of 40: a single-centre adult cohort. | Preda V | European journal of endocrinology | 2014 | PMID: 25184284 |
| Familial isolated pituitary adenomas (FIPA) and the pituitary adenoma predisposition due to mutations in the aryl hydrocarbon receptor interacting protein (AIP) gene. | Beckers A | Endocrine reviews | 2013 | PMID: 23371967 |
| [Algorithm of clinical assessment of the hemostasiogram indices in surgical practice]. | Dutkevich IG | Vestnik khirurgii imeni I. I. Grekova | 2012 | PMID: 23038925 |
| Germline mutations of AIP gene in somatotropinomas resistant to somatostatin analogues. | Oriola J | European journal of endocrinology | 2012 | PMID: 23038625 |
| High prevalence of AIP gene mutations following focused screening in young patients with sporadic pituitary macroadenomas. | Tichomirowa MA | European journal of endocrinology | 2011 | PMID: 21753072 |
| Familial isolated pituitary adenomas: from genetics to therapy. | Guaraldi F | Clinical and translational science | 2011 | PMID: 21348957 |
| Characterization of aryl hydrocarbon receptor interacting protein (AIP) mutations in familial isolated pituitary adenoma families. | Igreja S | Human mutation | 2010 | PMID: 20506337 |
| Genetic factors in the development of pituitary adenomas. | Vandeva S | Endocrine development | 2010 | PMID: 19955762 |
| Aryl hydrocarbon receptor interacting protein (AIP) gene mutation analysis in children and adolescents with sporadic pituitary adenomas. | Georgitsi M | Clinical endocrinology | 2008 | PMID: 18410548 |
| The role of the aryl hydrocarbon receptor-interacting protein gene in familial and sporadic pituitary adenomas. | Leontiou CA | The Journal of clinical endocrinology and metabolism | 2008 | PMID: 18381572 |
| Germline inactivating mutations of the aryl hydrocarbon receptor-interacting protein gene in a large cohort of sporadic acromegaly: mutations are found in a subset of young patients with macroadenomas. | Cazabat L | European journal of endocrinology | 2007 | PMID: 17609395 |
| Familial acromegaly: studies in three families. | McCarthy MI | Clinical endocrinology | 1990 | PMID: 2200621 |
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Text-mined citations for rs139407567 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 20, 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.