Submissions for variant NM_000352.6(ABCC8):c.1732_1746dup (p.Ala578_Leu582dup)

dbSNP: rs757650373

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000201873	SCV002067528	likely pathogenic	not provided	2020-08-07	criteria provided, single submitter	clinical testing	This sequence change is a 15 base pair duplication in exon 12, c.1732_1746dup. This in-frame duplication is predicted to result in the duplication of five amino acid residues, p.Ala578_Leu582dup. This specific duplication has been described in two patients with congenital hyperinsulinism (CHI) in the compound heterozygous state with another pathogenic variant in the same gene (PMIDs: 23275527, 27188453). It has also been described in the heterozygous state (paternally inherited) in two unelated patients with CHI (PMIDs: 20685672, 16429405). The c.1732_1746dup sequence change has been described in three heterozygous individuals in gnomAD which corresponds to a low population frequency of 0.0012% (dbSNP rs757650373).
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002266933	SCV002522349	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 (rs757650373) in neonatal diabetes yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002266932	SCV002522350	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 (rs757650373) in MODY yet.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003321542	SCV004026554	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The c.1732_1746dup variant in ABCC8 has been previously reported in 5 individuals with hyperinsulinemic hypoglycemia (PMID: 20685672, 16429405, 23275527, 27188453), and has been seen in 0.009% (2/34592) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs757650373). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 217848) and has been interpreted as a variant of uncertain significance by Clinical Genomics (Uppaluri K&H Personalized Medicine Clinic), and as likely pathogenic/pathogenic by Genetic Services Laboratory (University of Chicago) and Genomic Diagnostic Laboratory (Division of Genomic Diagnostics, Children's Hospital of Philadelphia). Of the 5 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variants in trans, which increases the likelihood that the c.1732_1746dup variant is pathogenic (Variation ID: 9086, PMID: 16429405). This variant is an insertion of 5 amino acids at position 582 and is not predicted to alter the protein reading-frame. It is unclear if this insertion will impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3, PM4, PM2 (Richards 2015).
Baylor Genetics	RCV003468927	SCV004207205	pathogenic	Type 2 diabetes mellitus	2024-03-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005042435	SCV005676387	likely pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-05-02	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000201873	SCV000256809	pathogenic	not provided	2015-10-07	no assertion criteria provided	clinical testing