Submissions for variant NM_000352.6(ABCC8):c.4412-13G>A

dbSNP: rs1008906426

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000667182	SCV000791598	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2017-05-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387141	SCV001587690	pathogenic	not provided	2023-03-29	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 551999). This variant is also known as c.4415-13G>A. This variant has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 20943781, 24145932, 25972930, 30186238). This variant has been reported in individual(s) with autosomal dominant familial hyperinsulinism (PMID: 28439221); however, the role of the variant in this condition is currently unclear. This variant is present in population databases (no rsID available, gnomAD 0.006%). This sequence change falls in intron 36 of the ABCC8 gene. It does not directly change the encoded amino acid sequence of the ABCC8 protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002233099	SCV002511483	pathogenic	Familial hyperinsulinism	2022-04-27	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.4412-13G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: One predict the variant abolishes the canonical 3' splice acceptor site. Two predict the variant weakens the canonical 3' acceptor site. Four predict the variant creates an alternate intronic 3' splice acceptor site that predicts the retention of eleven intronic nucleotides leading to a frameshift in the protein sequence. At least one publication reports experimental evidence on a minigene splicing assay that this variant affects mRNA splicing leading to an out of frame alteration consistent with the computational predictions (example, Saint-Martin_2021). The variant allele was found at a frequency of 4e-06 in 251406 control chromosomes. c.4412-13G>A has been reported in the literature as homozygous, compound heterozygous and carrier genotypes in individuals affected with focal or diffuse histologies of Congenital Hyperinsulinism (example, Bellanne-Chantelot_2010, Ohkubo_2005, Yorifuji_2013, Saint-Martin_2021). These data indicate that the variant is very likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Mendelics	RCV002249395	SCV002516203	likely pathogenic	Type 2 diabetes mellitus	2022-05-04	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000667182	SCV002759353	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2022-12-07	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000667182	SCV004026568	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The c.4412-13G>A variant in ABCC8 has been reported in at least 9 individuals with hyperinsulinemic hypoglycemia (PMID: 20685672, 30186238, 33688939, 25972930, 21968111, 26504129, 28439221, 33240318, 15807877), and has been identified in 0.005% (1/18392) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1008906426). 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#: 551999) and has been interpreted as pathogenic or likely pathogenic by multiple sources. Of the 9 affected individuals, 4 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the c.4412-13G>A variant is pathogenic (Variation ID: 434053, 959844; PMID: 20685672, 30186238, 26504129, 33240318). A minigene assay performed on affected tissue shows evidence of intron retention after exon 36 (PMID: 33410562). This variant is located in the 5' splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine/rule out pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very_strong, PS3_moderate, PP3, PP2_supporting (Richards 2015).
Baylor Genetics	RCV002249395	SCV004196771	pathogenic	Type 2 diabetes mellitus	2024-01-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000667182	SCV004807890	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2024-03-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835906	SCV002085281	pathogenic	Hereditary hyperinsulinism	2017-09-20	no assertion criteria provided	clinical testing