ClinVar

Description

The c.1630+1G>T variant in ABCC8 has been reported in at least 12 individuals with hyperinsulinemic hypoglycemia (PMID: 20685672, 33688939, 10426386, 27334808, 17236890, 10338089, 9618169, 31997554), and has been identified in 0.005% (1/21648) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs773306994). 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: 370604) and has been interpreted as pathogenic by Counsyl, Invitae, and Natera Inc. Of the 12 affected individuals, 6 were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans, which increases the likelihood that the c.1630+1G>T variant is pathogenic (PMID: 20685672, 33688939, 10426386, 17236890, 9618169). This variant is located in the 3' splice region. SpliceAI predictions indicate use of an out-of-frame cryptic splice site 70 bases from the intron-exon boundary, providing evidence that this variant may cause a frameshift and lead to a premature termination codon downstream. This alteration is then predicted to lead to a truncated or absent protein. However, this information is not predictive enough to determine pathogenicity. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very-strong, PM2_supporting, PVS1 (Richards 2015).