Submissions for variant NM_000352.6(ABCC8):c.892C>T (p.Arg298Cys)

gnomAD frequency: 0.00011  dbSNP: rs144705160

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780805	SCV000918367	uncertain significance	not specified	2018-03-23	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.892C>T (p.Arg298Cys) results in a non-conservative amino acid change located in the transmembrane domain of the ABC transporter type 1 of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 275726 control chromosomes in the gnomAD database, including 1 homozygotes. This frequency is not significantly higher than expected for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.00021 vs 0.0034), allowing no conclusion about variant significance. c.892C>T has been reported in the literature in individuals affected with Congenital Hyperinsulinism (Mohnike_2014, Snider_2013). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV001311739	SCV001502031	uncertain significance	not provided	2021-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001311739	SCV001986306	uncertain significance	not provided	2023-03-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24401662, 26221353, 34426522, 33046911, 31291970, 23275527, 33300273)
Genetic Services Laboratory, University of Chicago	RCV000780805	SCV002069792	uncertain significance	not specified	2017-07-11	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002493426	SCV002776979	uncertain significance	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2021-07-08	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001311739	SCV003496281	uncertain significance	not provided	2022-09-20	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 298 of the ABCC8 protein (p.Arg298Cys). This variant is present in population databases (rs144705160, gnomAD 0.08%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individual(s) with ABCC8-related conditions (PMID: 23275527, 24401662, 31291970, 33046911, 33300273). ClinVar contains an entry for this variant (Variation ID: 633025). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	RCV002535684	SCV003706043	uncertain significance	Inborn genetic diseases	2021-08-27	criteria provided, single submitter	clinical testing	(Mohnike, 2014) Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Molecular Genetics, Royal Melbourne Hospital	RCV003994115	SCV004812430	uncertain significance	Maturity onset diabetes mellitus in young	2022-11-03	criteria provided, single submitter	clinical testing	This sequence change in ABCC8 is predicted to replace arginine with cysteine at codon 298, p.(Arg298Cys). The arginine residue is moderately conserved (61/100 vertebrates, UCSC), and is located in the linker region adjacent to the transmembrane domain. There is a large physicochemical difference between arginine and cysteine. The highest population minor allele frequency in the population database gnomAD v2.1 is 0.045% (16/35,434, including one homozygote) in the Latino/Admixed American population. This variant has been reported in at least three heterozygous probands with young-onset diabetes mellitus type 2 (PMID: 33300273, 31291970, 33046911). Multiple lines of computational evidence have conflicting predictions for the missense substitution (4/6 algorithms predict this variant to be deleterious). Based on the classification scheme RMH Modified ACMG Guidelines v1.5.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: none.
Natera, Inc.	RCV001276286	SCV001462395	uncertain significance	Hereditary hyperinsulinism	2020-04-22	no assertion criteria provided	clinical testing