Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001851769 | SCV002235500 | pathogenic | not provided | 2023-01-16 | criteria provided, single submitter | clinical testing | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. ClinVar contains an entry for this variant (Variation ID: 9094). This variant is also known as p.Arg1353Pro. This missense change has been observed in individuals with autosomal recessive diffuse or focal hyperinsulinism (PMID: 9769320, 23275527, 24814349, 31291970). This variant is present in population databases (rs28936370, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 1352 of the ABCC8 protein (p.Arg1352Pro). Experimental studies have shown that this missense change affects ABCC8 function (PMID: 15356046). For these reasons, this variant has been classified as Pathogenic. |
| Fulgent Genetics, |
RCV002504772 | SCV002816807 | likely pathogenic | Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 | 2021-08-20 | criteria provided, single submitter | clinical testing | |
| Broad Center for Mendelian Genomics, |
RCV000009662 | SCV004026516 | likely pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2023-08-16 | criteria provided, single submitter | curation | 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). |
| OMIM | RCV000009662 | SCV000029880 | pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 1998-10-01 | no assertion criteria provided | literature only |