Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Genetic Services Laboratory, |
RCV001818043 | SCV002065897 | uncertain significance | not specified | 2021-11-22 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.2975G>C, in exon 25 that results in an amino acid change, p.Arg992Pro. This sequence change has been described in the gnomAD database with a frequency of 0.007% in the non-Finnish European subpopulation (dbSNP rs201499958). The p.Arg992Pro change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. The p.Arg992Pro substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This variant has been identified in one individual with a clinical diagnosis of MODY (PMID: 34393998 ) and in an individual with dyslipidemia (PMID: 320416110). A different variant affecting the same amino acid, p.Arg992Cys, has been identified in an infant with diabetes mellitus, inherited from an asymptomatic mother (PMID: 27522937). Experimental studies of the p.Arg992Cys variant demonstrated this sequence change impacted the function of the ABCC8 protein (PMID: 30861254). Due to insufficient evidence and the lack of functional studies, the clinical significance of the p.Arg992Pro change remains unknown at this time. |
| Fulgent Genetics, |
RCV002506859 | SCV002814633 | uncertain significance | Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 | 2022-03-29 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV002542707 | SCV003285276 | uncertain significance | not provided | 2021-08-27 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with proline at codon 992 of the ABCC8 protein (p.Arg992Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is present in population databases (rs201499958, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with ABCC8-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV002542708 | SCV003728003 | uncertain significance | Inborn genetic diseases | 2021-08-23 | criteria provided, single submitter | clinical testing | The c.2975G>C (p.R992P) alteration is located in exon 25 (coding exon 25) of the ABCC8 gene. This alteration results from a G to C substitution at nucleotide position 2975, causing the arginine (R) at amino acid position 992 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |