ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.4628T>C (p.Leu1543Pro)

gnomAD frequency: 0.00001  dbSNP: rs72559713
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Total submissions: 8
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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, University of Chicago RCV000169185 SCV000592989 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2015-11-09 criteria provided, single submitter clinical testing
Invitae RCV000800626 SCV000940355 pathogenic not provided 2024-01-14 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, 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 2022-03-24 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard 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).
PreventionGenetics, part of Exact Sciences RCV003390882 SCV004120041 likely pathogenic ABCC8-related condition 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, Inc. RCV001826866 SCV002085248 pathogenic Hereditary hyperinsulinism 2021-05-20 no assertion criteria provided clinical testing

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