ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.1562G>A (p.Arg521Gln)

gnomAD frequency: 0.00011  dbSNP: rs368114790
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000144978 SCV000192014 uncertain significance Diabetes mellitus 2013-07-12 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV001262624 SCV001440561 uncertain significance Type 2 diabetes mellitus 2019-01-01 criteria provided, single submitter clinical testing This variant was identified as compound heterozygous.
MGZ Medical Genetics Center RCV001262624 SCV002579575 uncertain significance Type 2 diabetes mellitus 2021-11-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002298483 SCV002598615 uncertain significance not specified 2023-06-28 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.1562G>A (p.Arg521Gln) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251160 control chromosomes, predominantly at a frequency of 0.00019 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not higher than predicted for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.0001 vs 0.0034), allowing no conclusion about variant significance. c.1562G>A has been reported in the literature in individuals affected with Hyperinsulinism without a family history for Congenital Hyperinsulinism (example: Calabria_2012, and Snider_2013). One publication listed this variant as medically actionable - likely pathogenic for AD hyperinsulinemia (Rego_2018), however, recent publications evaluated it as VUS (example: Franco_2019 and Maron_2021). In addition, co-occurrences with other pathogenic variant (HNF1A c.160C>T, p.Arg54X) has been reported in a male patient diagnosed with Maturity Onset Diabetes Of The Young (Ivanoshchuk_2021). These reports do not provide unequivocal conclusions about association of the variant with Congenital Hyperinsulinism. 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: 23275527, 22855730, 30487145, 32027066, 33587123, 33477506). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS: n=3; Likely pathogenic: n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Athena Diagnostics Inc RCV002505120 SCV002817243 uncertain significance not provided 2019-08-27 criteria provided, single submitter clinical testing This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV002505120 SCV004026002 uncertain significance not provided 2022-03-15 criteria provided, single submitter clinical testing
Genetics and Molecular Pathology, SA Pathology RCV003447502 SCV004175695 uncertain significance Hyperinsulinemic hypoglycemia, familial, 1 2022-12-13 criteria provided, single submitter clinical testing The ABCC8 c.1562G>A variant is classified as VUS (PM1) The ABCC8 c.1562G>A variant is a single nucleotide change in exon 10/39 of the ABCC8 gene, which is predicted to change the amino acid arginine at position 521 in the protein to glutamine. This variant is located in the conserved ABC-membrane domain (PM1). The variant has been reported in dbSNP (rs368114790), in population databases (gnomAD 17/152162, 0 homs) and in the HGMD database as disease causing (CM1212138). It has been reported as Conflicting interpretations of pathogenicity by other diagnostic laboratories (ClinVar Variation ID: 157683). The variant has been reported in teh scientific literature in patients with hyperinsulinism and as a variant of uncertain significance (PMID:21378087, 22855730, 23275527, 3202066).
Snyder Lab, Genetics Department, Stanford University RCV000722048 SCV000853091 likely pathogenic Familial hyperinsulinism 2017-01-01 flagged submission research

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