Total submissions: 8
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Counsyl | RCV000169185 | SCV000220427 | likely pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2014-06-19 | criteria provided, single submitter | literature only | |
Genetic Services Laboratory, |
RCV000169185 | SCV000592989 | likely pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2015-11-09 | criteria provided, single submitter | clinical testing | |
Labcorp Genetics |
RCV000800626 | SCV000940355 | pathogenic | not provided | 2024-07-03 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1543 of the ABCC8 protein (p.Leu1543Pro). This variant is present in population databases (rs72559713, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 11867634, 15562009, 23275527). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Leu1544Pro. ClinVar contains an entry for this variant (Variation ID: 188836). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCC8 protein function. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 11867634). For these reasons, this variant has been classified as Pathogenic. |
Fulgent Genetics, |
RCV002492687 | SCV002797611 | pathogenic | Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 | 2024-06-15 | criteria provided, single submitter | clinical testing | |
Broad Center for Mendelian Genomics, |
RCV000169185 | SCV004026514 | likely pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2023-08-16 | criteria provided, single submitter | curation | The p.Leu1543Pro variant in ABCC8 has been reported in at least 7 individuals with hyperinsulinemic hypoglycemia (PMID: 17378627, 15562009, 31997554, 23275527, 11867634) and has been identified in 0.003% (3/251104) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs72559713). 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#: 188836) and has been interpreted as likely pathogenic or pathogenic by Counsyl, Invitae, Genetic Services Laboratory (University of Chicago), and Natera Inc. Of the 7 affected individuals, 2 were compound heterozygotes that carried a pathogenic variant in trans. This increases the likelihood that the p.Leu1543Pro variant is pathogenic (VariationID: 370604; PMID: 17378627, 31997554). In vitro functional studies provide some evidence that the p.Leu1543Pro variant may impact protein function (PMID: 11867634). 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_moderate, PP3, PM2_supporting (Richards 2015). |
Prevention |
RCV004535147 | SCV004120041 | likely pathogenic | ABCC8-related disorder | 2022-08-23 | criteria provided, single submitter | clinical testing | The ABCC8 c.4628T>C variant is predicted to result in the amino acid substitution p.Leu1543Pro. This variant is located in the C-loop2 domain which is a interaction surface for intracellular partners (Kelly L et al 2010. PubMed ID: 20799350). This variant, also known as p.Leu1544Pro, has been reported along with a second pathogenic variant in ABCC8 in several individuals with hyperinsulinism (Taschenberger G et al 2002. PubMed ID: 11867634; Henwood MJ et al 2004. PubMed ID: 15562009; Snider KE et al 2012. PubMed ID: 23275527; ). Functional studies showed that this variant interferes with normal trafficking of KATP channels (Taschenberger G et al 2002. PubMed ID: 11867634). This variant is reported in 0.0026% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-17414656-A-G). This variant is interpreted as likely pathogenic. |
Baylor Genetics | RCV003468836 | SCV004190524 | pathogenic | Type 2 diabetes mellitus | 2023-09-12 | criteria provided, single submitter | clinical testing | |
Natera, |
RCV001826866 | SCV002085248 | pathogenic | Hereditary hyperinsulinism | 2021-05-20 | no assertion criteria provided | clinical testing |