Submissions for variant NM_006412.4(AGPAT2):c.475C>T (p.Arg159Cys)

gnomAD frequency: 0.00430  dbSNP: rs142993240

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000193694	SCV000246334	benign	not specified	2018-11-07	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV000445508	SCV000537070	benign	Monogenic diabetes	2019-02-22	criteria provided, single submitter	research	ACMG criteria: BS1 (1% in gnomAD AJ population, 0.5% overall MAF in gnomAD; disease prevalence 1:10 million gives MAF of 0.03%), BS2 (8 homozygotes in gnomAD) [REVEL 0.582, BP4 (3 predictors), PP3 (6 predictors)= conflicting evidence, not using]; heterozygotes mutation found in brother and sister with lipodytrophy phenotype Simsir et al. 2015 ""Heterozygous AGPAT2 Mutation, Diabetes, and Lipodystrophy in Extremities"" (no PMID)= benign
Invitae	RCV000883942	SCV001027285	benign	not provided	2024-01-18	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001167076	SCV001329520	benign	Congenital generalized lipodystrophy type 1	2017-04-27	criteria provided, single submitter	clinical testing	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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000193694	SCV002103808	benign	not specified	2022-02-19	criteria provided, single submitter	clinical testing	Variant summary: AGPAT2 c.475C>T (p.Arg159Cys) results in a non-conservative amino acid change located in the Phospholipid/glycerol acyltransferase domain (IPR002123) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0051 in 248240 control chromosomes in the gnomAD database, including 9 homozygotes. The observed variant frequency is approximately 5.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in AGPAT2 causing Congenital Generalized Lipodystrophy phenotype (0.00087), strongly suggesting that the variant is benign. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Mayo Clinic Laboratories, Mayo Clinic	RCV000883942	SCV002541046	uncertain significance	not provided	2021-12-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000883942	SCV004163912	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	AGPAT2: BS2
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV001167076	SCV004698173	uncertain risk allele	Congenital generalized lipodystrophy type 1		criteria provided, single submitter	research	Potent mutations in AGPAT2 gene are associated with Congenital generalized lipodystrophy, type 1, which can present with insulin resistance, fatty liver and diabetes. rs142993240 variant is prevalent with Congenital Generalized Lipoatrophy. However, the role of this rs142993240 particular variant is yet to be ascertained.
PreventionGenetics, part of Exact Sciences	RCV003917731	SCV004736081	benign	AGPAT2-related disorder	2019-05-01	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).