Submissions for variant NM_000352.6(ABCC8):c.2522G>A (p.Arg841Gln)

dbSNP: rs547150342

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Diagnostics Services (NGS), CSIR - Centre For Cellular And Molecular Biology	RCV000669690	SCV001160745	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2020-01-13	criteria provided, single submitter	clinical testing	The NM_000352.6:c.2522G>A variant is not present in publicly available database, Exome Variant Server (EVS). The variant is present in 1000 Genomes, Exome Aggregation Consortium (ExAC), Genome Aggregation Database (gnomAD) and dbSNP at a very low frequency (MAF<=0.0001) in heterozygous state. The variant is not present in our in-house exome database. The variant was earlier reported to Human Genome Mutation database (HGMD ID: CM112697) in other similarly affected individuals [Banerjee et al., Eur J Endocrinol 2011]. In-silico pathogenicity prediction programs like SIFT, Polyphen2, MutationTaster2, CADD etc. predicted this variant as likely deleterious. Hence as per ACMG guidelines the variant has been classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000669690	SCV001440562	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2019-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861780	SCV002233264	pathogenic	not provided	2022-05-13	criteria provided, single submitter	clinical testing	This missense change has been observed in individuals with clinical features of autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 21378087, 24686051). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 841 of the ABCC8 protein (p.Arg841Gln). This variant is not present in population databases (gnomAD no frequency). This variant is also known as c.2525G>A p.Arg842Gln. ClinVar contains an entry for this variant (Variation ID: 554121). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. This variant disrupts the p.Arg841 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been observed in individuals with ABCC8-related conditions (PMID: 11395395, 32202736), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV004556812	SCV002515469	uncertain risk allele	Neonatal diabetes mellitus	2024-05-27	criteria provided, single submitter	research	This variant is found to be a potent moderate impact, variant with a CADD score of 29.8 and sufficient scientific evidence of gene-disease correlation. However, since this is not a high impact variant and no variant evidence, this variant is reclassified as Uncertain risk allele.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002245557	SCV002515470	uncertain risk allele	Maturity onset diabetes mellitus in young	2024-05-29	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 ( rs547150342) in MODY yet. This variant is found to be a potent moderate impact, deleterious variant with a CADD score of 29.8 and sufficient scientific evidence to support gene-disease correlation. However, since this is not a high impact variant and has no variant evidence, this variant is reclassified as Uncertain Risk Allele
Baylor Genetics	RCV003472116	SCV004202037	likely pathogenic	Type 2 diabetes mellitus	2023-05-20	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005049645	SCV005676336	likely pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-03-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000669690	SCV000794467	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2017-09-26	flagged submission	clinical testing