ClinVar

Description

The p.Arg1379Cys (sometimes called p.Arg1380Cys) variant in ABCC8 has been reported in 7 individuals with Monogenic Diabetes, segregated with disease in 4 affected relatives from 1 family (PMID: 16885549, 17446535, 25306193), and has been identified in 0.003286% (1/30434) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852673). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. Trio analysis showed this variant to be de novo with unconfirmed maternity and paternity in one individual reported in the literature (PMID: 17446535). This variant has also been reported pathogenic in ClinVar (Variation ID: 9105). In vitro functional studies provide some evidence that the p.Arg1379Cys variant may slightly increase the rate of ATP hydrolysis (PMID: 18025464). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Three additional variants with a different amino acid change at the same position, (p.Arg1379His, p.Arg1379Leu and p.Arg1379Ser), have been reported in association with disease in ClinVar or have been curated likely pathogenic or as variants of uncertain significance by our study, supporting that a change at this position may not be tolerated (Variation ID: 35615, 35614). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM6, PM5_supporting, PS3_supporting, PM2_Supporting, PP3, PS4_Supporting, PP1 (Richards 2015).