ClinVar Miner

Submissions for variant NM_006412.4(AGPAT2):c.493-1G>C

gnomAD frequency: 0.00001  dbSNP: rs606231168
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Unidad de Genómica Médica UC, Pontificia Universidad Católica de Chile RCV000007009 SCV000902518 pathogenic Congenital generalized lipodystrophy type 1 2013-03-04 criteria provided, single submitter research Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by extreme reduction of white adipose tissue (WAT) mass. CGL type 1 is the most frequent form and is caused by mutations in AGPAT2. Genetic and clinical studies were performed in two affected sisters of a Chilean family. These patients have notoriously dissimilar metabolic abnormalities that correlate with differential levels of circulating leptin and soluble leptin receptor fraction. Sequencing of AGPAT2 exons and exon-intron boundaries revealed two homozygous mutations in both sisters. Intronic c.493-1G>C mutation destroy a conserved splicing site that likely leads to exon 4 skipping and deletion of whole AGPAT2 substrate binding domain. In silico protein modeling provided insights of the mechanisms of lack of catalytic activity owing to both mutations.
DASA RCV000007009 SCV002073789 likely pathogenic Congenital generalized lipodystrophy type 1 2022-02-05 criteria provided, single submitter clinical testing The c.493-1G>C variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts <10% of protein - PVS1_moderate. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 6630; PMID: 24498038, 15181077) - PS4_supporting. The variant is present at low allele frequencies population databases (rs606231168 – gnomAD 0.00006570%; ABraOM no frequency - - PM2_supporting. The c.493-1G>C was detected in trans with a pathogenic variant (PMID: 24498038) - PM3. In summary, the currently available evidence indicates that the variant is likely pathogenic.
OMIM RCV000007009 SCV000027205 pathogenic Congenital generalized lipodystrophy type 1 2004-06-01 no assertion criteria provided literature only
GeneReviews RCV000007009 SCV000490119 not provided Congenital generalized lipodystrophy type 1 no assertion provided literature only

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