Submissions for variant NM_000352.6(ABCC8):c.916C>T (p.Arg306Cys)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
MVZ Dr. Eberhard & Partner Dortmund	RCV002465967	SCV002760212	uncertain significance	not provided	2022-04-05	criteria provided, single submitter	clinical testing	In this missense variant Arginine is replaced with Cysteine at position 306 in ABCC8. Algorithms developed to predict the effect of missense changes in protein structure (e.g. Varsome, Mutation Taster) support a deleterious effect on the gene or gene product but the allelic frequency of about 0.003 % seems to be to high for a very rare and dominant inherited disease. This missense variant was reported in patients with diabetes of unknown type who were part of a Diabetes Type 2 cohort or related to patients with congenital hyperinsulinism (PMID: 29207974, PMID: 33300273, PMID: 33046911) and there are also some patients described with congenital hyperinsulinism where this variant occurred in compound heterozygosity (PMID: 28929366, PMID: 32928245, PMID: 34304300). The evidence at hand is not sufficient to determine the role of this variant in diabetes.
Ambry Genetics	RCV002571393	SCV003718210	uncertain significance	Inborn genetic diseases	2021-07-19	criteria provided, single submitter	clinical testing	The c.916C>T (p.R306C) alteration is located in exon 6 (coding exon 6) of the ABCC8 gene. This alteration results from a C to T substitution at nucleotide position 916, causing the arginine (R) at amino acid position 306 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003464565	SCV004205040	uncertain significance	Type 2 diabetes mellitus	2022-01-30	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002465967	SCV004547191	likely pathogenic	not provided	2023-12-12	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 306 of the ABCC8 protein (p.Arg306Cys). This variant is present in population databases (rs751228166, gnomAD 0.01%). This missense change has been observed in individuals with autosomal recessive congenital hyperinsulinism (PMID: 23275527, 32928245, 34304300). ClinVar contains an entry for this variant (Variation ID: 1802689). 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 with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.