NM_003977.4(AIP):c.911G>A (p.Arg304Gln) AND Somatotroph adenoma

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Jun 22, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000508590.19

Allele description [Variation Report for NM_003977.4(AIP):c.911G>A (p.Arg304Gln)]

NM_003977.4(AIP):c.911G>A (p.Arg304Gln)

Gene:

AIP:aryl hydrocarbon receptor interacting protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

11q13.2

Genomic location:

Preferred name:

NM_003977.4(AIP):c.911G>A (p.Arg304Gln)

HGVS:

NC_000011.10:g.67490911G>A
NG_008969.1:g.12878G>A
NM_001302959.2:c.734G>A
NM_001302960.2:c.*51G>A
NM_003977.4:c.911G>AMANE SELECT
NP_001289888.1:p.Arg245Gln
NP_003968.3:p.Arg304Gln
LRG_460t1:c.911G>A
LRG_460:g.12878G>A
NC_000011.9:g.67258382G>A
NM_003977.2:c.911G>A
NM_003977.3:c.911G>A

Protein change:

R245Q; ARG304GLN

Links:

OMIM: 605555.0008; dbSNP: rs104894190

NCBI 1000 Genomes Browser:

rs104894190

Molecular consequence:

NM_001302960.2:c.*51G>A - 3 prime UTR variant - [Sequence Ontology: SO:0001624]
NM_001302959.2:c.734G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003977.4:c.911G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Somatotroph adenoma (PITA1)
Synonyms:: ISOLATED FAMILIAL SOMATOTROPINOMA; SOMATOTROPHINOMA, FAMILIAL; Pituitary tumor, growth hormone-secreting, somatic; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007052; MedGen: C4538355; Orphanet: 314777; Orphanet: 963; OMIM: 102200

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MIGS Cultured Bacterial/Archaeal sample from Citrobacter sp. Cpo147
MIGS Cultured Bacterial/Archaeal sample from Citrobacter sp. Cpo147

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txid2985152[Organism:noexp] (1)
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000373587	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Likely benign (Jul 27, 2017)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 27153395, 20530095, 20506337, 17360484, 18381572, 23633209, 22720333, 25184284 Citation Link,
SCV001138359	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Uncertain significance (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV002525988	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Jun 22, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000373587

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Likely benign
(Jul 27, 2017)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Citation Link,

SCV001138359

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Uncertain significance
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV002525988

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

criteria provided, single submitter

(St. Jude Assertion Criteria 2020)

Uncertain significance
(Jun 22, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
Turkish	germline	yes	1	not provided	not provided	not provided	not provided	research

Citations

PubMed

Phenotypic and genotypic features of a large kindred with a germline AIP variant.

Dal J, Nielsen EH, Klose M, Feldt-Rasmussen U, Andersen M, Vang S, Korbonits M, Jørgensen JOL.

Clin Endocrinol (Oxf). 2020 Aug;93(2):146-153. doi: 10.1111/cen.14207. Epub 2020 May 18.

PubMed [citation]

PMID:: 32324286

Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.

Maxwell KN, Hart SN, Vijai J, Schrader KA, Slavin TP, Thomas T, Wubbenhorst B, Ravichandran V, Moore RM, Hu C, Guidugli L, Wenz B, Domchek SM, Robson ME, Szabo C, Neuhausen SL, Weitzel JN, Offit K, Couch FJ, Nathanson KL.

Am J Hum Genet. 2016 May 5;98(5):801-817. doi: 10.1016/j.ajhg.2016.02.024.

PubMed [citation]

PMID:: 27153395
PMCID:: PMC4863474

See all PubMed Citations (10)

Details of each submission

From OMIM, SCV000025348.3

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

Description

In a 26-year-old Polish patient with Cushing disease due to an ACTH-secreting pituitary adenoma (PITA1; 102200), Georgitsi et al. (2007) identified a heterozygous c.911G-A transition in exon 6 of the AIP gene, resulting in an arg304-to-gln (R304Q) substitution.

In a large Danish kindred comprising 52 family members spanning 5 generations, Dal et al. (2020) identified 31 individuals with heterozygosity for the R304Q mutation. Based on 2 cases of somatotropinomas among the mutation carriers, the disease penetrance was 6%. Two individuals with homozygosity for R304Q were reported in the gnomAD database.

#	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

From Illumina Laboratory Services, Illumina, SCV000373587.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

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.

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

From Aziz Sancar Institute of Experimental Medicine, Istanbul University, SCV000693856.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	Turkish	1	not provided	not provided	research	PubMed (1)

Description

a variant already in ClinVar database associated with clinical findings in a Turkish patient

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

From Mendelics, SCV001138359.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

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

From St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV002525988.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

The AIP c.911G>A (p.Arg304Gln) missense change has a maximum subpopulation frequency of 0.14% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function. A ß-galactosidase activity assay in yeast showed a mild reduction of ß-galactosidase activity compared to wildtype (PMID: 20506337). This variant has been reported in individuals with pituitary adenoma (PMID: 17360484, 17609395, 18381572, 19366855, 20506337). 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.

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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000025348	OMIM	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None	Pathogenic (Mar 6, 2007)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 17360484, 32324286
SCV000693856	Aziz Sancar Institute of Experimental Medicine, Istanbul University	flagged submission Reason: Outlier claim with insufficient supporting evidence Notes: None	Pathogenic (Mar 9, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000025348

OMIM

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

Pathogenic
(Mar 6, 2007)

germline

literature only

PubMed (2)
[See all records that cite these PMIDs]

SCV000693856

Aziz Sancar Institute of Experimental Medicine, Istanbul University

flagged submission

Reason: Outlier claim with insufficient supporting evidence

Notes: None

Pathogenic
(Mar 9, 2018)

germline

research

PubMed (1)
[See all records that cite this PMID]

Last Updated: May 12, 2024

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