Submissions for variant NM_000352.6(ABCC8):c.3544C>T (p.Arg1182Trp)

gnomAD frequency: 0.00001  dbSNP: rs797045209

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192916	SCV000246296	pathogenic	Diabetes mellitus, transient neonatal, 2	2014-11-24	criteria provided, single submitter	clinical testing
Molecular Genetics, Madras Diabetes Research Foundation	RCV002051825	SCV002318410	likely pathogenic	Neonatal diabetes mellitus		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002500586	SCV002806626	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-06-18	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517038	SCV003522326	pathogenic	not provided	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1182 of the ABCC8 protein (p.Arg1182Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of autosomal dominant neonatal diabetes mellitus (PMID: 17446535, 32893419). In at least one individual the variant was observed to be de novo. This variant is also known as R1183W. ClinVar contains an entry for this variant (Variation ID: 210076). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCC8 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg1182 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16885549, 17446535, 22749773, 24622368). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987437	SCV004804523	pathogenic	Familial hyperinsulinism	2024-01-12	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.3544C>T (p.Arg1182Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251376 control chromosomes. c.3544C>T, also described as p.R1183W, has been reported in the literature in multiple individuals affected with Neonatal diabetes mellitus, and in at-least three cases, this variant arose de novo (Flanagan_2007, Ngoc_2021). Parents carrying this variant were also reported to be unaffected (Flanagan_2007). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17446535, 34566892). ClinVar contains an entry for this variant (Variation ID: 210076. Pathogenic/Likely pathogenic). Based on the evidence outlined above, the variant was classified as pathogenic.
Department of Endocrinology, Antwerp University Hospital	RCV001640282	SCV001519034	pathogenic	Type 2 diabetes mellitus	2020-11-15	no assertion criteria provided	clinical testing	This is a variant with a reported allele frequency of 0.000003978 according to GnomAD. This, together with Clinvar reports on pathogenicity and variant effect predictor strengthens the indirect evidence for causality. The present mutation has mostly been associated with neonatal diabetes (Flanagan 2007, Batra 2009, Kong 2010, Bonnefond 2013, Beltrand 2015, Zhang 2015, Hashimoto 2016) and in only 3 papers reporting a MODY12 (Reilly 2019, Novak 2020, Gurtunca 2020).