Description
The p.Arg1352Pro variant in ABCC8 has been reported in 4 individuals with hyperinsulinemic hypoglycemia (PMID: 23275527, 9769320, 24814349, 10828824, 10338089) and has been identified in 0.002% (2/113748) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs28936370). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 9094) and has been interpreted as likely pathogenic by Invitae and OMIM. Of the 4 affected individuals, 2 were compound heterozygotes that carried a pathogenic or likely pathogenic variants in trans, which increases the likelihood that the p.Arg1352Pro variant is pathogenic (VariationID: 553929; PMID: 9769320, 24814349). In vitro functional studies provide some evidence that the p.Arg1352Pro variant may impact protein function (PMID: 15356046). 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. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_strong, PS3_supporting, PP3, PM2_supporting (Richards 2015).
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
