Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate
The NM_000352.6(ABCC8):c.1562G>A(p.Arg521Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,613,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R521R) has been classified as Likely benign.
ABCC8 (HGNC:59): (ATP binding cassette subfamily C member 8) The protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MRP subfamily which is involved in multi-drug resistance. This protein functions as a modulator of ATP-sensitive potassium channels and insulin release. Mutations in the ABCC8 gene and deficiencies in the encoded protein have been observed in patients with hyperinsulinemic hypoglycemia of infancy, an autosomal recessive disorder of unregulated and high insulin secretion. Mutations have also been associated with non-insulin-dependent diabetes mellitus type II, an autosomal dominant disease of defective insulin secretion. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2020]
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM1
?
PM1 - Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation
In a topological_domain Cytoplasmic (size 61) in uniprot entity ABCC8_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_000352.6
PM2
?
PM2 - Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium
Very rare variant in population databases, with high coverage;
BP4
?
BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (MetaRNN=0.19832951).
Uncertain significance, criteria provided, single submitter
clinical testing
Athena Diagnostics
Aug 27, 2019
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. -
Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Aug 17, 2023
Reported without a second ABCC8 variant in hyperinsulinism cohorts in published literature (Calabria et al. 2012; Snider et al., 2013; De Franco et al., 2020); however, patient-specific clinical information not provided; Identified in a patient with features of MODY who also had a pathogenic variant in the HNF1A gene (Ivanoshchuk et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 23275527, 30487145, 22855730, 32027066, 33477506, 33587123) -
Uncertain significance, criteria provided, single submitter
clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Mar 15, 2022
- -
Type 2 diabetes mellitus Uncertain:2
Uncertain significance, criteria provided, single submitter
clinical testing
MGZ Medical Genetics Center
Nov 17, 2021
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Uncertain significance, criteria provided, single submitter
clinical testing
Institute of Human Genetics, University of Leipzig Medical Center
Jan 01, 2019
This variant was identified as compound heterozygous. -
Familial hyperinsulinism Pathogenic:1
Likely pathogenic, flagged submission
research
Snyder Lab, Genetics Department, Stanford University
Jan 01, 2017
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not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Jun 28, 2023
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. -
Diabetes mellitus Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Uncertain significance, criteria provided, single submitter
clinical testing
Genetics and Molecular Pathology, SA Pathology
Dec 13, 2022
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). -