Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1PM2BP4_StrongBP6
The NM_000352.6(ABCC8):c.4563G>T(p.Lys1521Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,614,172 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars).
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 Likely_benign. Variant got -1 ACMG points.
PM1
In a domain ABC transporter 2 (size 234) in uniprot entity ABCC8_HUMAN there are 33 pathogenic changes around while only 3 benign (92%) in NM_000352.6
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.017162055).
BP6
Variant 11-17393742-C-A is Benign according to our data. Variant chr11-17393742-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 434043.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=6}. Variant chr11-17393742-C-A is described in Lovd as [Likely_benign].
Likely benign, criteria provided, single submitter
clinical testing
Labcorp Genetics (formerly Invitae), Labcorp
Jan 27, 2024
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Uncertain significance, criteria provided, single submitter
clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Jul 17, 2017
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Uncertain significance, criteria provided, single submitter
clinical testing
Athena Diagnostics
Jun 07, 2018
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Uncertain significance, criteria provided, single submitter
clinical testing
GeneDx
Apr 26, 2021
In silico analysis supports that this missense variant does not alter protein structure/function; Previously reported in two children with obesity (Foucan et al., 2018); This variant is associated with the following publications: (PMID: 29216354) -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter
clinical testing
Genetic Services Laboratory, University of Chicago
Nov 24, 2015
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ABCC8-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided
clinical testing
PreventionGenetics, part of Exact Sciences
May 12, 2024
The ABCC8 c.4563G>T variant is predicted to result in the amino acid substitution p.Lys1521Asn. This variant was reported in patients with type 2 diabetes diagnosed at age 37 and 42 years (Tarasov et al. 2008. PubMed ID: 18346985). It was also reported in a study of monogenic obesity (Foucan et al. 2018. PubMed ID: 29216354). Tarasov et al. study suggested that the p.Lys1521Asn change may not be responsible for diabetes, but its pathogenicity wasn’t actually entirely conclusive. Its minor allele frequency reaches ~0.4% in Africans. The amino acid residue p.Lys1521 has been highly conserved during evolution. In summary, we classify it as a variant of uncertain significance due to insufficient evidence. -
Maturity onset diabetes mellitus in young Uncertain:1
Uncertain significance, criteria provided, single submitter
research
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
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Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs142272833) in MODY yet. -
Transitory neonatal diabetes mellitus Uncertain:1
Uncertain significance, criteria provided, single submitter
research
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic
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Mutations in ABCC8 gene are associated with both neonatal diabetes mellitus as well as MODY. Patients with this mutation may have a better response to sulfonylureas. However, no sufficient evidence is found to ascertain the role of this particular variant (rs142272833) in neonatal diabetes yet. -
Monogenic diabetes Benign:1
Benign, criteria provided, single submitter
research
Personalized Diabetes Medicine Program, University of Maryland School of Medicine
Jun 29, 2018
ACMG criteria: [PP3 (4 predictors), BP4 (6 predictors), REVEL = 0.392, conflicting evidence so not using], BS2 (15 cases and 14 controls in type2diabetesgenetics.org, ABCC8 causes AD and AR d/o), BS3 (PMID: 18346985, functional assays showed no different from wild type) = Benign -