NM_000306.4(POU1F1):c.515G>A (p.Arg172Gln) AND Pituitary hormone deficiency, combined, 1

Germline classification:: Likely pathogenic (2 submissions)
Last evaluated:: May 22, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000014584.28

Allele description [Variation Report for NM_000306.4(POU1F1):c.515G>A (p.Arg172Gln)]

NM_000306.4(POU1F1):c.515G>A (p.Arg172Gln)

Gene:

POU1F1:POU class 1 homeobox 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p11.2

Genomic location:

Preferred name:

NM_000306.4(POU1F1):c.515G>A (p.Arg172Gln)

HGVS:

NC_000003.12:g.87262160C>T
NG_008225.2:g.19428G>A
NM_000306.4:c.515G>AMANE SELECT
NM_001122757.3:c.593G>A
NP_000297.1:p.Arg172Gln
NP_001116229.1:p.Arg198Gln
NC_000003.11:g.87311310C>T
NM_000306.2:c.515G>A
NM_000306.3:c.515G>A

Protein change:

R172Q; ARG172GLN

Links:

OMIM: 173110.0013; dbSNP: rs104893765

NCBI 1000 Genomes Browser:

rs104893765

Molecular consequence:

NM_000306.4:c.515G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001122757.3:c.593G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Pituitary hormone deficiency, combined, 1 (CPHD1)
Synonyms:: Pituitary hormone deficiency, combined or isolated, 1
Identifiers:: MONDO: MONDO:0024464; MedGen: C2751608; OMIM: 613038

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000034838	OMIM	no assertion criteria provided	Pathogenic (Aug 1, 2005)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV002521151	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (May 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 15928241, 27541381, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000034838

OMIM

no assertion criteria provided

Pathogenic
(Aug 1, 2005)

germline

literature only

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

SCV002521151

3billion

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(May 22, 2022)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

Help

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
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Novel mutations within the POU1F1 gene associated with variable combined pituitary hormone deficiency.

Turton JP, Reynaud R, Mehta A, Torpiano J, Saveanu A, Woods KS, Tiulpakov A, Zdravkovic V, Hamilton J, Attard-Montalto S, Parascandalo R, Vella C, Clayton PE, Shalet S, Barton J, Brue T, Dattani MT.

J Clin Endocrinol Metab. 2005 Aug;90(8):4762-70. Epub 2005 May 31.

PubMed [citation]

PMID:: 15928241

Joint laxity in homozygotes for severe POU1F1 mutations.

Shamseldin HE, Maddirevula S, Nabil A, Al-Fadhil S, Al Tala S, Alkuraya FS.

Am J Med Genet A. 2016 Dec;170(12):3356-3358. doi: 10.1002/ajmg.a.37941. Epub 2016 Aug 19. No abstract available.

PubMed [citation]

PMID:: 27541381

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000034838.2

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

Description

In 2 Maltese sibs with combined pituitary hormone deficiency (CPHD1; 613038), Turton et al. (2005) identified a novel 515G-A transition within exon 4 of the POU1F1 gene that resulted in substitution of arginine by glutamine at codon 172 in the POU-S (R172Q). These patients were compound heterozygous for this mutation and E230K (172110.0012). Functional studies revealed that the R172Q mutation is associated with a reduction in DNA binding and transactivation.

#	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 3billion, SCV002521151.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.84; 3Cnet: 0.80). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with POU1F1 related disorder (ClinVar ID: VCV000013614 / PMID: 15928241). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 15928241). The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:15928241, 27541381). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

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

Last Updated: Sep 3, 2023

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