VCV000006625.20 - ClinVar

NM_006412.4(AGPAT2):c.589-2A>G

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_006412.4(AGPAT2):c.589-2A>G

Variation ID: 6625 Accession: VCV000006625.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.3 9: 136674809 (GRCh38) [ NCBI UCSC ] 9: 139569261 (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	Nov 29, 2014	Feb 4, 2024	Dec 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_006412.4:c.589-2A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NM_001012727.2:c.493-2A>G		splice acceptor
NC_000009.12:g.136674809T>C
NC_000009.11:g.139569261T>C
NG_008090.1:g.17651A>G
NG_118315.1:g.135T>C

... more HGVS ... less HGVS

Protein change

Other names

IVS4AS, A-G, -2

Canonical SPDI

NC_000009.12:136674808: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.

0.00100 (C)

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

The Genome Aggregation Database (gnomAD), exomes 0.00010

Exome Aggregation Consortium (ExAC) 0.00016

Trans-Omics for Precision Medicine (TOPMed) 0.00042

The Genome Aggregation Database (gnomAD) 0.00043

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00054

1000 Genomes Project 0.00100

1000 Genomes Project 30x 0.00125

Links

ClinGen: CA277944 OMIM: 603100.0002 dbSNP: rs116807569 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.
AGPAT2		-	-	GRCh38 GRCh37	197	278

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.
Congenital generalized lipodystrophy type 1	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Aug 3, 2023	RCV000007004.18
not provided	Pathogenic (3)	criteria provided, single submitter	Mar 13, 2022	RCV001579685.5
Congenital generalized lipodystrophy	Pathogenic (1)	criteria provided, single submitter	Dec 13, 2023	RCV003488328.1

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.
Pathogenic (Aug 06, 2015)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Lipodystrophy, congenital generalized, type 1 Affected status: yes Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000246335.1 First in ClinVar: Oct 05, 2015 Last updated: Oct 05, 2015
Pathogenic (Aug 03, 2023)	criteria provided, single submitter (ICSLVariantClassificationCriteria RUGD 01 April 2020) Method: clinical testing	Congenital generalized lipodystrophy type 1 Affected status: unknown Allele origin: unknown	Illumina Laboratory Services, Illumina Accession: SCV004101314.1 First in ClinVar: Nov 11, 2023 Last updated: Nov 11, 2023	Publications: PubMed (6) PubMed: 14557463‚ 34318892‚ 32280377‚ 12765973‚ 31416577‚ 11967537 Comment: The AGPAT2 c.589-2A>G variant, also referred to as IVS4-2A>G, results a substitution within the consensus splice acceptor site. This variant is predicted to result in … (more) The AGPAT2 c.589-2A>G variant, also referred to as IVS4-2A>G, results a substitution within the consensus splice acceptor site. This variant is predicted to result in a frameshift and premature termination with addition of novel amino acids (PMID: 11967537; 12765973). The c.589-2A>G variant has been reported in at least 24 unrelated individuals in a homozygous state and at least 11 unrelated individuals in either a confirmed or presumed compound heterozygous state with phenotypes consistent with congenital generalized lipodystrophy (PMID: 11967537; 12765973; 14557463; 31416577; 32280377; 34318892). This variant segregated with disease in multiple families (PMID: 11967537; 12765973 14557463). The c.589-2A>G variant is reported at a frequency of 0.001496 in the African/African American population of the Genome Aggregation Database (version 3.1.2). Based on the available evidence, the c.589-2A>G variant is classified as pathogenic for congenital generalized lipodystrophy. (less)
Pathogenic (Apr 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congenital generalized lipodystrophy type 1 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV001752661.2 First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022
Pathogenic (Mar 13, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV002104454.2 First in ClinVar: Mar 19, 2022 Last updated: Mar 04, 2023	Comment: Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: … (more) Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30266686, 11967537, 25525159, 19278620, 26072926, 22344438, 15181077, 32041611, 12765973, 32280377, SchweisbergerC2021[Abstract], 34033296, 31416577, 30296183, 30595509, 34318892) (less)
Pathogenic (Dec 13, 2023)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Congenital generalized lipodystrophy Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004241087.1 First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024	Publications: PubMed (2) PubMed: 11967537‚ 12765973 Comment: Variant summary: AGPAT2 c.589-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to … (more) Variant summary: AGPAT2 c.589-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. The variant allele was found at a frequency of 0.0001 in 198966 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in AGPAT2 causing Congenital Generalized Lipodystrophy (0.0001 vs 0.00087), allowing no conclusion about variant significance. c.589-2A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Generalized Lipodystrophy (examples: Agarwal_2002 and Magre_2003). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11967537, 12765973). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Pathogenic (Jun 01, 2004)	no assertion criteria provided Method: literature only	LIPODYSTROPHY, CONGENITAL GENERALIZED, TYPE 1 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027200.3 First in ClinVar: Apr 04, 2013 Last updated: Jul 01, 2023	Publications: PubMed (2) PubMed: 11967537‚ 15181077 Comment on evidence: In affected members of 5 families of African descent with Berardinelli-Seip congenital lipodystrophy-1 (CGL1; 608594), Agarwal et al. (2002) found either homozygosity or compound heterozygosity … (more) In affected members of 5 families of African descent with Berardinelli-Seip congenital lipodystrophy-1 (CGL1; 608594), Agarwal et al. (2002) found either homozygosity or compound heterozygosity for a splice site mutation in the AGPAT2 gene (IVS4-2A-G) resulting in a frameshift and a premature termination at codon 228 (Gln196fsTer228). In 2 African American families living in the U.S., the mutation was present in homozygous state. In another U.S. African American family, it was present in compound heterozygous state with a 1-bp insertion, 377insT, causing a frameshift, Leu126fsTer146 (603100.0003). In a Caribbean family living in the U.K., it was found in compound heterozygous state with a missense mutation, leu228 to pro (603100.0004). In an African Caribbean family living in Trinidad, it was present in compound heterozygous state with a 3-bp deletion, 418delTTC (603100.0005), resulting in loss of phenylalanine-140. The 4 homozygous individuals in 2 families varied in age from 23 to 37 years. Agarwal et al. (2002) found that the splice site mutation in the 5 families of African origin was on an allele that had the same haplotype for 7 markers extending 33 kb, suggesting a common ancestral mutation. Fu et al. (2004) found this mutation in an African American female with congenital generalized lipodystrophy and in 3 African American sibs with cystic angiomatosis of the long bones (a phenotype designated Brunzell syndrome; see 608594). In the African American sibship, the 2 females had primary amenorrhea. (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808138.1 First in ClinVar: Aug 26, 2021 Last updated: Aug 26, 2021
Pathogenic (-)	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: SCV001928462.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
not provided (-)	no classification provided Method: literature only	Congenital generalized lipodystrophy type 1 Affected status: yes Allele origin: germline	GeneReviews Accession: SCV000490123.2 First in ClinVar: Oct 05, 2015 Last updated: Oct 01, 2022	Publications: BookShelf: NBK1212 BookShelf: NBK1212

Comment:

The AGPAT2 c.589-2A>G variant, also referred to as IVS4-2A>G, results a substitution within the consensus splice acceptor site. This variant is predicted to result in a frameshift and premature termination with addition of novel amino acids (PMID: 11967537; 12765973). The c.589-2A>G variant has been reported in at least 24 unrelated individuals in a homozygous state and at least 11 unrelated individuals in either a confirmed or presumed compound heterozygous state with phenotypes consistent with congenital generalized lipodystrophy (PMID: 11967537; 12765973; 14557463; 31416577; 32280377; 34318892). This variant segregated with disease in multiple families (PMID: 11967537; 12765973 14557463). The c.589-2A>G variant is reported at a frequency of 0.001496 in the African/African American population of the Genome Aggregation Database (version 3.1.2). Based on the available evidence, the c.589-2A>G variant is classified as pathogenic for congenital generalized lipodystrophy.

Comment:

Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 30266686, 11967537, 25525159, 19278620, 26072926, 22344438, 15181077, 32041611, 12765973, 32280377, SchweisbergerC2021[Abstract], 34033296, 31416577, 30296183, 30595509, 34318892)

Comment:

Variant summary: AGPAT2 c.589-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 3' acceptor site. The variant allele was found at a frequency of 0.0001 in 198966 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in AGPAT2 causing Congenital Generalized Lipodystrophy (0.0001 vs 0.00087), allowing no conclusion about variant significance. c.589-2A>G has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with Congenital Generalized Lipodystrophy (examples: Agarwal_2002 and Magre_2003). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 11967537, 12765973). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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
Approach to Diagnosing a Pediatric Patient With Severe Insulin Resistance in Low- or Middle-income Countries.	van Heerwaarde AA	The Journal of clinical endocrinology and metabolism	2021	PMID: 34318892
Leu124Serfs*26, a novel AGPAT2 mutation in congenital generalized lipodystrophy with early cardiovascular complications.	Montenegro Junior RM	Diabetology & metabolic syndrome	2020	PMID: 32280377
The worldwide mutational landscape of Berardinelli-Seip congenital lipodystrophy.	Craveiro Sarmento AS	Mutation research. Reviews in mutation research	2019	PMID: 31416577
Berardinelli-Seip Congenital Lipodystrophy.	Adam MP	-	2016	PMID: 20301391
Mutations in Gng3lg and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects.	Fu M	The Journal of clinical endocrinology and metabolism	2004	PMID: 15181077
Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy.	Agarwal AK	The Journal of clinical endocrinology and metabolism	2003	PMID: 14557463
Prevalence of mutations in AGPAT2 among human lipodystrophies.	Magré J	Diabetes	2003	PMID: 12765973
AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34.	Agarwal AK	Nature genetics	2002	PMID: 11967537

Text-mined citations for rs116807569 ...

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 Feb 14, 2024

ClinVar Genomic variation as it relates to human health

NM_006412.4(AGPAT2):c.589-2A>G

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs116807569 ...