Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001388604 | SCV001589661 | pathogenic | not provided | 2022-02-05 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Cys1000*) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). This variant is present in population databases (rs192863214, gnomAD 0.0009%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1075098). This premature translational stop signal has been observed in individual(s) with congenital hyperinsulinism (PMID: 24434300). |
| Broad Center for Mendelian Genomics, |
RCV003321835 | SCV004026533 | likely pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2023-08-16 | criteria provided, single submitter | curation | The p.Cys1000Ter variant in ABCC8 has been reported in at least 2 individuals with hyperinsulinemic hypoglycemia (PMID: 24434300, 25008049), and has been identified in 0.0009% (1/111072) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs192863214). 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: 1075098) and has been interpreted as Pathogenic by Invitae. This nonsense variant leads to a premature termination codon at position 1000, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. 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: PVS1, PM2 (Richards 2015). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004801004 | SCV005422507 | pathogenic | Familial hyperinsulinism | 2024-10-09 | criteria provided, single submitter | clinical testing | Variant summary: ABCC8 c.3000C>A (p.Cys1000X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4e-06 in 248338 control chromosomes (gnomAD). c.3000C>A has been reported in the literature in individuals affected with Congenital Hyperinsulinism (e.g. Su_2014). The following publication has been ascertained in the context of this evaluation (PMID: 24434300). ClinVar contains an entry for this variant (Variation ID: 1075098). Based on the evidence outlined above, the variant was classified as pathogenic. |