VCV000896986.30 - ClinVar

NM_000939.4(POMC):c.394C>G (p.Pro132Ala)

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.

(10)

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(4); Benign(2); 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_000939.4(POMC):c.394C>G (p.Pro132Ala)

Variation ID: 896986 Accession: VCV000896986.30

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2p23.3 2: 25161491 (GRCh38) [ NCBI UCSC ] 2: 25384360 (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 31, 2020	Oct 20, 2024	Apr 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000939.4:c.394C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000930.1:p.Pro132Ala	missense
NM_000939.3:c.394C>G
NM_001035256.3:c.394C>G	NP_001030333.1:p.Pro132Ala	missense
NM_001319204.2:c.394C>G	NP_001306133.1:p.Pro132Ala	missense
NM_001319205.2:c.394C>G	NP_001306134.1:p.Pro132Ala	missense
NC_000002.12:g.25161491G>C
NC_000002.11:g.25384360G>C
NG_008997.1:g.12200C>G

... more HGVS ... less HGVS

Protein change

P132A

Other names

Canonical SPDI

NC_000002.12:25161490:G: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 30x 0.00016

1000 Genomes Project 0.00020

Trans-Omics for Precision Medicine (TOPMed) 0.00107

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00127

Exome Aggregation Consortium (ExAC) 0.00132

Links

dbSNP: rs8192606 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.
POMC		-	-	GRCh38 GRCh37	170	227

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.
Obesity due to pro-opiomelanocortin deficiency	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001139997.5
Obesity	Uncertain significance (1)	criteria provided, single submitter	Apr 27, 2017	RCV001139998.5
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Apr 18, 2024	RCV001580566.23
not specified	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	May 4, 2022	RCV001819845.6
POMC-related disorder	Uncertain significance (1)	no assertion criteria provided	Aug 8, 2024	RCV004538359.2

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 (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Inherited obesity Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001300203.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 18091355‚ 16459314 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Obesity due to pro-opiomelanocortin deficiency Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001300202.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (2) PubMed: 18091355‚ 16459314 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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Uncertain significance (Apr 18, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001817854.2 First in ClinVar: Sep 08, 2021 Last updated: Sep 16, 2024	Comment: In silico analysis supports that this missense variant does not alter protein structure/function; Variant reported in multiple patients with severe obesity but also reported in … (more) In silico analysis supports that this missense variant does not alter protein structure/function; Variant reported in multiple patients with severe obesity but also reported in patients from the control group in the published literature (PMID: 28377240, 16459314, 18091355, 29970488); This variant is associated with the following publications: (PMID: 16459314, 25448875, 18091355, 29970488, 28377240, 35562395) (less)
Uncertain significance (Feb 15, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV002070876.1 First in ClinVar: Jan 29, 2022 Last updated: Jan 29, 2022
Benign (May 04, 2022)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Mendelics Accession: SCV002519066.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022
Benign (Dec 11, 2023)	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: SCV002323481.3 First in ClinVar: Apr 08, 2022 Last updated: Feb 14, 2024
Likely benign (Dec 01, 2022)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004138690.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: POMC: BS2 Number of individuals with the variant: 1
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001922139.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001930401.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Uncertain significance (Aug 08, 2024)	no assertion criteria provided Method: clinical testing	POMC-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004116899.3 First in ClinVar: Nov 20, 2023 Last updated: Oct 08, 2024	Comment: The POMC c.394C>G variant is predicted to result in the amino acid substitution p.Pro132Ala. This variant has been reported in several individuals with obesity (Lee … (more) The POMC c.394C>G variant is predicted to result in the amino acid substitution p.Pro132Ala. This variant has been reported in several individuals with obesity (Lee et al. 2006. PubMed ID: 16459314; Table S1, Kleinendorst et al. 2018. PubMed ID: 29970488; Dubern et al. 2008. PubMed ID: 18091355; Shah et al. 2023. PubMed ID: 36864747; Nordang et al. 2017. PubMed ID: 28377240) but also in control subjects (Nordang et al. 2017. PubMed ID: 28377240). In vitro functional studies showed this variant did not reduce protein function and could cause increased function (Supplemental Data Set 3, Shah et al. 2023. PubMed ID: 36864747). This variant is reported in 0.21% of alleles in individuals of European (Finnish) descent in gnomAD, including one homozygous individual. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)

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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Comment:

In silico analysis supports that this missense variant does not alter protein structure/function; Variant reported in multiple patients with severe obesity but also reported in patients from the control group in the published literature (PMID: 28377240, 16459314, 18091355, 29970488); This variant is associated with the following publications: (PMID: 16459314, 25448875, 18091355, 29970488, 28377240, 35562395)

Comment:

The POMC c.394C>G variant is predicted to result in the amino acid substitution p.Pro132Ala. This variant has been reported in several individuals with obesity (Lee et al. 2006. PubMed ID: 16459314; Table S1, Kleinendorst et al. 2018. PubMed ID: 29970488; Dubern et al. 2008. PubMed ID: 18091355; Shah et al. 2023. PubMed ID: 36864747; Nordang et al. 2017. PubMed ID: 28377240) but also in control subjects (Nordang et al. 2017. PubMed ID: 28377240). In vitro functional studies showed this variant did not reduce protein function and could cause increased function (Supplemental Data Set 3, Shah et al. 2023. PubMed ID: 36864747). This variant is reported in 0.21% of alleles in individuals of European (Finnish) descent in gnomAD, including one homozygous individual. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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
Mutational analysis of the pro-opiomelanocortin gene in French obese children led to the identification of a novel deleterious heterozygous mutation located in the alpha-melanocyte stimulating hormone domain.	Dubern B	Pediatric research	2008	PMID: 18091355
A POMC variant implicates beta-melanocyte-stimulating hormone in the control of human energy balance.	Lee YS	Cell metabolism	2006	PMID: 16459314

Text-mined citations for rs8192606 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000939.4(POMC):c.394C>G (p.Pro132Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs8192606 ...