Description
The p.Asp310Asn variant in ABCC8 has been previously reported in 3 individuals with hyperinsulinemic hypoglycemia (PMID: 16429405, 17236890, 27908292) and has been seen in 0.006% (2/34590) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs769569410). 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: 585352) and has been interpreted as likely pathogenic by Fulgent Genetics, DASA, Natera Inc, Athena Diagnostics Inc, and Invitae. Of the 3 affected individuals, 1 was a compound heterozygote that carried a reported likely pathogenic variants in trans, which increases the likelihood that the p.Asp310Asn variant is pathogenic (PMID: 17236890). In vitro functional studies provide some evidence that the p.Asp310Asn variant may slightly impact protein function (PMID: 18596924, 20427569). 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, PP3, PM2, PS3_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 |
