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

gnomAD frequency: 0.00043  dbSNP: rs116807569

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000007004	SCV000246335	pathogenic	Congenital generalized lipodystrophy type 1	2015-08-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000007004	SCV001752661	pathogenic	Congenital generalized lipodystrophy type 1	2022-04-07	criteria provided, single submitter	clinical testing
GeneDx	RCV001579685	SCV002104454	pathogenic	not provided	2022-03-13	criteria provided, single submitter	clinical testing	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)
Illumina Laboratory Services, Illumina	RCV000007004	SCV004101314	pathogenic	Congenital generalized lipodystrophy type 1	2023-08-03	criteria provided, single submitter	clinical testing	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488328	SCV004241087	pathogenic	Congenital generalized lipodystrophy	2023-12-13	criteria provided, single submitter	clinical testing	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.
OMIM	RCV000007004	SCV000027200	pathogenic	Congenital generalized lipodystrophy type 1	2004-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000007004	SCV000490123	not provided	Congenital generalized lipodystrophy type 1		no assertion provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001579685	SCV001808138	pathogenic	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001579685	SCV001928462	pathogenic	not provided		no assertion criteria provided	clinical testing