Submissions for variant NM_000352.6(ABCC8):c.579+2T>A

dbSNP: rs1449198328

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000671080	SCV000796022	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2017-11-30	criteria provided, single submitter	clinical testing
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002254171	SCV002522679	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 (rs1449198328) in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002254172	SCV002522680	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 (rs1449198328) in neonatal diabetes yet.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000671080	SCV004026599	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The c.579+2T>A variant in ABCC8 has not been previously reported in the literature in individuals with hyperinsulinemic hypoglycemia, but has been identified in 0.003% (1/32402) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1449198328). 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 (VariationID: 555287) and has been interpreted as likely pathogenic by Counsyl. This variant is located in the 3' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. There is an in-frame cryptic splice site 6 bases from the intron-exon boundary, providing evidence that this variant may delete 2 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the c.579+2T>A variant is uncertain. ACMG/AMP Criteria applied: PVS1_strong, PM2_supporting (Richards 2015).
Baylor Genetics	RCV003472134	SCV004194985	likely pathogenic	Type 2 diabetes mellitus	2023-09-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003994076	SCV004813557	likely pathogenic	Familial hyperinsulinism	2024-02-07	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.579+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the 5' canonical splicing donor site. One predict the variant strengthens a cryptic 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.3e-06 in 229928 control chromosomes. To the best of our knowledge, c.579+2T>A has not been reported in the literature in individuals affected with Familial Hyperinsulinism. This variant at a heterozygous was found in a female individual from a cohort of gamete donors and couples undergoing IVF (Capalbo_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31589614). ClinVar contains an entry for this variant (Variation ID: 555287). Based on the evidence outlined above, the variant was classified as likely pathogenic.