ClinVar Miner

Submissions for variant NM_006412.4(AGPAT2):c.662-2A>C

gnomAD frequency: 0.00001  dbSNP: rs1131691791
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000494035 SCV000582843 pathogenic not provided 2017-05-19 criteria provided, single submitter clinical testing The c.662-2A>C variant in the AGPAT2 gene has been reported previously in the homozygous state in an individual with Berardinelli-Seip syndrome (Agarwal et al., 2002). This splice site variant destroys the canonical splice acceptor site in intron 5. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.662-2A>C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.662-2A>C as a pathogenic variant.
Fulgent Genetics, Fulgent Genetics RCV002506195 SCV002809690 likely pathogenic Congenital generalized lipodystrophy type 1 2021-10-14 criteria provided, single submitter clinical testing
3billion RCV002506195 SCV005905911 pathogenic Congenital generalized lipodystrophy type 1 2024-01-17 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. The predicted truncated protein may be shortened by more than 10%. In silico tools predict the variant to alter splicing and produce an abnormal transcript [Splice AI: 1.00 (spliceogenicity >=0.2, non-spliceogenicity <0.1)]. The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 11967537). The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000430117 /PMID: 11967537). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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