Submissions for variant NM_000352.6(ABCC8):c.4563G>T (p.Lys1521Asn)

gnomAD frequency: 0.00130  dbSNP: rs142272833

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000500617	SCV000592977	uncertain significance	not specified	2015-11-24	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514132	SCV000610875	uncertain significance	not provided	2017-07-17	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000514132	SCV000840603	uncertain significance	not provided	2018-06-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000514132	SCV001015717	likely benign	not provided	2025-01-27	criteria provided, single submitter	clinical testing
Personalized Diabetes Medicine Program, University of Maryland School of Medicine	RCV001174390	SCV001337528	benign	Monogenic diabetes	2018-06-29	criteria provided, single submitter	research	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
GeneDx	RCV000514132	SCV001873775	uncertain significance	not provided	2025-02-12	criteria provided, single submitter	clinical testing	Reported in two individuals with obesity, one of whom also had impaired fasting glucose (PMID: 29216354); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: Deng2023[preprint], 29216354)
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002244966	SCV002512178	uncertain significance	Maturity onset diabetes mellitus in young		criteria provided, single submitter	research	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.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002244967	SCV002512179	uncertain significance	Transitory neonatal diabetes mellitus		criteria provided, single submitter	research	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.
PreventionGenetics, part of Exact Sciences	RCV004735573	SCV005356421	uncertain significance	ABCC8-related disorder	2024-05-12	no assertion criteria provided	clinical testing	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.