ClinVar Genomic variation as it relates to human health

The frequency of this variant in the general population is consistent with pathogenicity. Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site. In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic.

A heterozygous 3' splice variation in intron 24 of the ABCC8 gene that affects the position 9 nucleotides upstream of acceptor splice site of exon 24 was detected. The observed variant has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant are possibly damaging by MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as likely pathogenic.

The c.2921-9G>A variant in ABCC8 has been reported in 5 individuals with hyperinsulinemic hypoglycemia (PMID: 14715863, 16357843, 20685672, 24814349, 33410562), and has been identified in 0.01% (4/33418) of Laitno/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs757171524). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 434048) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago), Athena Diagnostics Inc, Foundation for Research in Genetics and Endocrinology (FRIGE's Institute of Human Genetics), Invitae, and Natera Inc. Of the five affected individuals, at least 2 were compound heterozygotes that carried a reported pathogenic variant in trans which increases the likelihood that the c.2921-9G>A variant is pathogenic (Variation ID: 196880; PMID: 16357843, 33410562). RNAseq analysis performed on affected tissue shows evidence of intron retention before exon 25 (PMID: 33410562). This variant is located in the 5’ splice region. 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, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_strong, PS3, PP3 (Richards 2015).

This sequence change falls in intron 24 of the ABCC8 gene. It does not directly change the encoded amino acid sequence of the ABCC8 protein. This variant is present in population databases (rs757171524, gnomAD 0.01%). This variant has been observed in individuals with autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 16357843, 33410562). This variant is also known as c.2924-9G>A. ClinVar contains an entry for this variant (Variation ID: 434048). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.