Total submissions: 7
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genomic Research Center, |
RCV000009663 | SCV000746732 | pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2017-12-18 | criteria provided, single submitter | clinical testing | |
| Counsyl | RCV000009663 | SCV000791010 | likely pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2017-04-27 | criteria provided, single submitter | clinical testing | |
| Illumina Laboratory Services, |
RCV000009663 | SCV000915514 | pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2019-01-12 | criteria provided, single submitter | clinical testing | The ABCC8 c.4258C>T (p.Arg1420Cys) missense variant, also referred to as c.4261C>T, (p.Arg1421Cys), has been reported in at least six studies in which it is found in a total of seven individuals with congenital hyperinsulinism, including in a homozygous state in three individuals (two of whom are siblings), in a compound heterozygous state in one individual, in a heterozygous state in one individual and in two individuals with unknown zygosity (Verkarre et al. 1998; de Lonlay-Debeney et al. 1999; Tanizawa et al. 2000; Bellanné-Chantelot et al. 2010; Snider et al. 2013; Kappor et al. 2013). The variant was absent from 480 control chromosomes and is not found in the 1000 Genomes Project, the Exome Sequencing Project, Exome Aggregation Consortium, or the Genome Aggregation Database. The Arg1420 residue is highly conserved. Matsuo et al. (2000) analyzed the functional effect of the p.Arg1420Cys variant and showed it lowers affinity for ATP and ADP binding and leads to enhanced insulin secretion. Tanizawa et al. (2000) transiently expressed the variant protein in COS-7 cells and showed inhibition of channel formation and function compared to wild type. Based on the collective evidence, the p.Arg1420Cys variant is classified as pathogenic for congenital hyperinsulinism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Invitae | RCV001235181 | SCV001407856 | pathogenic | not provided | 2023-06-09 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1420 of the ABCC8 protein (p.Arg1420Cys). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 10615958, 10993895, 26246406). 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: 9095). This variant is also known as p.Arg1421Cys. This missense change has been observed in individuals with clinical features of dyslipidemia and/or familial hyperinsulinemia (PMID: 9769320, 10615958, 17378627, 32041611). |
| Baylor Genetics | RCV003473070 | SCV004204074 | likely pathogenic | Type 2 diabetes mellitus | 2023-03-08 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000009663 | SCV000029881 | pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2000-12-29 | no assertion criteria provided | literature only | |
| Natera, |
RCV001831557 | SCV002077483 | likely pathogenic | Hereditary hyperinsulinism | 2020-01-23 | no assertion criteria provided | clinical testing |