ClinVar Miner

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

gnomAD frequency: 0.00270  dbSNP: rs200091822
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
PreventionGenetics,PreventionGenetics 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
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.

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