Submissions for variant NM_000352.6(ABCC8):c.1332+4del

gnomAD frequency: 0.00128  dbSNP: rs587783164

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000306595	SCV000369386	likely benign	Permanent neonatal diabetes mellitus	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000363722	SCV000369387	likely benign	Transient Neonatal Diabetes, Dominant	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000271496	SCV000369388	likely benign	Hyperinsulinism, Dominant/Recessive	2016-06-14	criteria provided, single submitter	clinical testing
GeneDx	RCV001564174	SCV001787295	likely benign	not provided	2020-04-20	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 16357843, 33410562)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001564174	SCV002490810	likely benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004019761	SCV004910935	likely benign	Inborn genetic diseases	2021-11-22	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700461	SCV005205059	likely benign	not specified	2024-06-07	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.1332+4delC alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Consensus agreement among computation tools predict no significant impact on normal splicing. This is consistent with functional studies using a minigene assay revealing no impact on splicing (Saint-Martin_2021). The variant allele was found at a frequency of 0.00097 in 251448 control chromosomes, predominantly at a frequency of 0.0016 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism, allowing no conclusion about variant significance. c.1332+4delC has been reported in the literature in individuals affected with Congenital Hyperinsulinism or Maturity-onset diabetes of the young (Suchi_2006, Saint-Martin_2021, Graff_2021). However, in some cases an alternative cause of disease was identified suggesting a benign role for this variant (Graff_2021). The following publications have been ascertained in the context of this evaluation (PMID: 34032641, 27913849, 33410562, 16357843). ClinVar contains an entry for this variant (Variation ID: 157682). Based on the evidence outlined above, the variant was classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV004577324	SCV000592988	likely benign	Hyperinsulinemic hypoglycemia, familial, 1	2016-01-08	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001564174	SCV001798420	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001564174	SCV001963890	likely benign	not provided		no assertion criteria provided	clinical testing