Submissions for variant NM_000352.6(ABCC8):c.-8G>T

gnomAD frequency: 0.00270  dbSNP: rs200091822

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000245897	SCV000303788	likely benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000264204	SCV000369428	likely benign	Permanent neonatal diabetes mellitus	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV000302860	SCV000369429	benign	Diabetes mellitus, transient neonatal, 2	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000359986	SCV000369430	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genetic Services Laboratory, University of Chicago	RCV000245897	SCV000592969	uncertain significance	not specified	2015-12-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001532154	SCV001747576	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	ABCC8: BS2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000245897	SCV002014891	benign	not specified	2021-10-12	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.-8G>T alters a non-conserved nucleotide located in the untranslated mRNA region upstream of the initiation codon. The variant allele was found at a frequency of 0.0026 in 290940 control chromosomes, including 3 homozygotes (gnomAD v2.1 and gnomAD v3.1 datasets). The variant was found predominantly within the Non-Finnish European subpopulation at a frequency of 0.0046. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism phenotype (0.0034), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.-8G>T has been reported in the literature in heterozygous state in individuals affected with neonatal diabetes, congenital hyperinsulinism and adult type 2 diabetes (Proks_2006, Banerjee_2011, Carreira_2021), however, in the reported neonatal/congenital cases, unaffected parents were also noted to carry the variant (Proks_2006, Banerjee_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001532154	SCV003921715	uncertain significance	not provided	2022-10-31	criteria provided, single submitter	clinical testing	Identified without a second variant in unrelated patients with congenital hyperinsulinism in published literature; however the variant was inherited from an unaffected parent in all cases (Proks et al., 2006; Banerjee et al., 2011); This variant is associated with the following publications: (PMID: 16613899, 33728157, 21378087)