VCV000346844.21 - ClinVar

NM_000306.4(POU1F1):c.370A>G (p.Met124Val)

Germline

Classification

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.

(9)

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(5); Benign(1); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000306.4(POU1F1):c.370A>G (p.Met124Val)

Variation ID: 346844 Accession: VCV000346844.21

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p11.2 3: 87264357 (GRCh38) [ NCBI UCSC ] 3: 87313507 (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	Dec 6, 2016	Oct 8, 2024	Jan 30, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000306.4:c.370A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000297.1:p.Met124Val	missense
NM_001122757.3:c.448A>G	NP_001116229.1:p.Met150Val	missense
NC_000003.12:g.87264357T>C
NC_000003.11:g.87313507T>C
NG_008225.2:g.17231A>G

... more HGVS ... less HGVS

Protein change

M124V, M150V

Other names

Canonical SPDI

NC_000003.12:87264356:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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 (C)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 0.00020

1000 Genomes Project 30x 0.00047

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00115

Trans-Omics for Precision Medicine (TOPMed) 0.00150

The Genome Aggregation Database (gnomAD) 0.00183

Exome Aggregation Consortium (ExAC) 0.00185

The Genome Aggregation Database (gnomAD), exomes 0.00197

Links

ClinGen: CA2501222 dbSNP: rs143373007 VarSome

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
Gene	OMIM	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.
POU1F1		-	-	GRCh38 GRCh37	210	234

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.
Combined Pituitary Hormone Deficiency, Recessive	Uncertain significance (1)	criteria provided, single submitter	Jun 14, 2016	RCV000286336.5
not specified	Benign (2)	criteria provided, single submitter	Jun 20, 2023	RCV000523099.4
Pituitary hormone deficiency, combined, 1	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Apr 6, 2022	RCV000764516.5
not provided	Conflicting interpretations of pathogenicity (3)	criteria provided, conflicting classifications	Jan 30, 2024	RCV000727655.14
POU1F1-related disorder	Likely benign (1)	no assertion criteria provided	Jul 23, 2019	RCV003912463.2

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 (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Combined Pituitary Hormone Deficiency, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000446381.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Jun 25, 2018)	criteria provided, single submitter (EGL ClinVar v180209 classification definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000854959.1 First in ClinVar: Dec 16, 2018 Last updated: Dec 16, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POU1F1 Number of individuals with the variant: 2 Sex: mixed
Uncertain significance (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pituitary hormone deficiency, combined, 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000895598.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Uncertain significance (Aug 20, 2020)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000617041.2 First in ClinVar: Dec 19, 2017 Last updated: Apr 17, 2019	Comment: Identified in a patient in published literature (Zhang et al., 2019) with septo-optic dysplasia and familial exudative vitreoretinopathy who also had a variant in another … (more) Identified in a patient in published literature (Zhang et al., 2019) with septo-optic dysplasia and familial exudative vitreoretinopathy who also had a variant in another gene that might contribute to the phenotype; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31755341) (less)
Benign (Jun 20, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004020548.1 First in ClinVar: Jul 29, 2023 Last updated: Jul 29, 2023	Publications: PubMed (1) PubMed: 31755341 Comment: Variant summary: POU1F1 c.370A>G (p.Met124Val) results in a conservative amino acid change located in the POU-specific domain (IPR000327) of the encoded protein sequence. Four of … (more) Variant summary: POU1F1 c.370A>G (p.Met124Val) results in a conservative amino acid change located in the POU-specific domain (IPR000327) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 282674 control chromosomes (gnomAD), predominantly at a frequency of 0.0027 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 115 fold of the estimated maximal expected allele frequency for a pathogenic variant in POU1F1 causing Combined Pituitary Hormone Deficiency (2.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.370A>G has been reported co-occuring with a VUS BCORL1 variant (ClinVar:386901) in the literature in one individual with Septo-optic dysplasia (de Morsier syndrome), which includes hypopituitarism (Zhang_2019). This report does not provide unequivocal conclusions about association of the variant with Combined Pituitary Hormone Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31755341). Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as benign. (less)
Uncertain significance (Apr 06, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pituitary hormone deficiency, combined, 1 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003809807.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely benign (Jan 30, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001034041.3 First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024
Uncertain significance (Feb 09, 2009)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital Accession: SCV000805017.1 First in ClinVar: Sep 13, 2018 Last updated: Sep 13, 2018
Likely benign (Jul 23, 2019)	no assertion criteria provided Method: clinical testing	POU1F1-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004730928.2 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).

Comment:

Identified in a patient in published literature (Zhang et al., 2019) with septo-optic dysplasia and familial exudative vitreoretinopathy who also had a variant in another gene that might contribute to the phenotype; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31755341)

Comment:

Variant summary: POU1F1 c.370A>G (p.Met124Val) results in a conservative amino acid change located in the POU-specific domain (IPR000327) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.002 in 282674 control chromosomes (gnomAD), predominantly at a frequency of 0.0027 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 115 fold of the estimated maximal expected allele frequency for a pathogenic variant in POU1F1 causing Combined Pituitary Hormone Deficiency (2.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.370A>G has been reported co-occuring with a VUS BCORL1 variant (ClinVar:386901) in the literature in one individual with Septo-optic dysplasia (de Morsier syndrome), which includes hypopituitarism (Zhang_2019). This report does not provide unequivocal conclusions about association of the variant with Combined Pituitary Hormone Deficiency. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31755341). Six ClinVar submitters have assessed the variant since 2014: five classified the variant as uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as 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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
FEVR phenotype associated with septo-optic dysplasia.	Zhang DL	Ophthalmic genetics	2019	PMID: 31755341
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=POU1F1	-	-	-	-

Text-mined citations for rs143373007 ...

These 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 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000306.4(POU1F1):c.370A>G (p.Met124Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs143373007 ...