Submissions for variant NM_000352.6(ABCC8):c.1252T>C (p.Cys418Arg)

gnomAD frequency: 0.00072  dbSNP: rs67254669

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000192390	SCV000246287	likely benign	not specified	2020-12-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000666629	SCV000790952	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2017-04-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710372	SCV000840582	uncertain significance	not provided	2022-09-22	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). This variant is statistically more frequent than in the general population, which is weak evidence this variant may be disease causing. Computational tools disagree on the variant's effect on normal protein function.
Fulgent Genetics, Fulgent Genetics	RCV000763720	SCV000894604	uncertain significance	Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus	2018-10-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001102903	SCV001259602	benign	Diabetes mellitus, transient neonatal, 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Laboratory Services, Illumina	RCV000666629	SCV001259603	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Illumina Laboratory Services, Illumina	RCV001102904	SCV001259604	benign	Permanent neonatal diabetes mellitus	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000192390	SCV001338158	uncertain significance	not specified	2022-12-13	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.1252T>C (p.Cys418Arg) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 251488 control chromosomes. This frequency is not higher than estimated for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.00069 vs 0.0034), allowing no conclusion about variant significance. c.1252T>C has been reported in patients with congenital hyperinsulinism (CHI) in the heterozygous state, without strong evidence for causality (e.g. Aguilar-Bryan_1999, Kapoor_2013, Snider_2013). An additional occurrence was reported in a patient with atypical Fanconi-Bickel syndrome (hyperinsulinemia compared to the typical diminished insulin secretion), who also carried known pathogenic mutations in SLC2A2; the mother was also a carrier of the variant and had no history of hypoglycemia therefore, allowing no conclusions about variant significance (Hoffman_2007). Additionally, p.C418R was reported as maternally inherited in a case of focal hyperinsulinemia (Otonkoski_2006). In this patient, the authors concluded that since the variant was apparently not expressed within the focal lesion it is likely not of functional importance. Lastly, the variant was detected in patients with MODY (Ozdemir_2018, Ates_2021, Demirci_2021), while it was also reported in association with type 2 diabetes (Riveline_2012, Mahajan_2018, Kim_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and nine ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV001336810	SCV001530307	uncertain significance	Type 2 diabetes mellitus	2018-10-15	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Pars Genome Lab	RCV001449652	SCV001652863	uncertain significance	Diabetes mellitus, permanent neonatal 3	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000710372	SCV001812790	uncertain significance	not provided	2024-07-23	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in unrelated probands with neonatal diabetes, type 2 diabetes, hyperinsulinism, or suspected MODY in published literature (PMID: 23345197, 22210575, 23275527, 30447144, 34462253); however, familial segregation information was not provided; In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 2165579, 17539904, 22210575, 16380471, 10204114, 30447144, 32640185, 32763092, 23275527, 30297969, 23345197, 32041611, 34426522, 34462253, 33108363, 34171966, 31604004, 20849526)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001336810	SCV001950071	uncertain significance	Type 2 diabetes mellitus	2021-10-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000710372	SCV003506815	uncertain significance	not provided	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 418 of the ABCC8 protein (p.Cys418Arg). This variant is present in population databases (rs67254669, gnomAD 0.1%). This missense change has been observed in individual(s) with autosomal dominant congenital hyperinsulinism and/or clinical features of ABCC8-related conditions (PMID: 22210575, 23345197, 30447144). ClinVar contains an entry for this variant (Variation ID: 210067). 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. 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.
PreventionGenetics, part of Exact Sciences	RCV004530090	SCV004118218	uncertain significance	ABCC8-related disorder	2023-07-25	criteria provided, single submitter	clinical testing	The ABCC8 c.1252T>C variant is predicted to result in the amino acid substitution p.Cys418Arg. This variant has been reported in both adult-onset diabetes and congenital hyperinsulinism, but its pathogenicity was not fully established (Riveline et al. 2012. PubMed ID: 22210575; Otonkoski et al. 2006. PubMed ID: 16380471; Kapoor et al. 2013. PubMed ID: 23345197). This variant is reported in 0.11% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-17470143-A-G), which may be too common to be a primary cause of disease. Although we suspect that this variant may possibly be benign, at this time the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Neuberg Centre For Genomic Medicine, NCGM	RCV001102903	SCV004176527	uncertain significance	Diabetes mellitus, transient neonatal, 2	2023-02-14	criteria provided, single submitter	clinical testing	The missense c.1252T>C (p.Cys418Arg) variant in ABCC8 gene has been reported previously in an individuals affected with ABCC8-related diabetes (Kapoor et al. 2013; Ateş et al. 2021). The p.Cys418Arg variant is reported with an allele frequency of 0.07% in the gnomAD exomes database. This variant has been reported to the ClinVar database as Benign / Likely Benign / Uncertain Significance. The amino acid change p.Cys418Arg in ABCC8 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Cys at position 418 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).
Natera, Inc.	RCV001272242	SCV001454044	uncertain significance	Hereditary hyperinsulinism	2020-09-16	no assertion criteria provided	clinical testing
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV003491936	SCV004240777	uncertain significance	Hypoglycemia		no assertion criteria provided	clinical testing