Submissions for variant NM_000352.6(ABCC8):c.96C>G (p.Asn32Lys)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Baylor Genetics	RCV003463382	SCV004206560	pathogenic	Type 2 diabetes mellitus	2023-02-26	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003553964	SCV004295396	pathogenic	not provided	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 32 of the ABCC8 protein (p.Asn32Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with congenital hyperinsulinism (PMID: 23275527, 28123437, 34055426). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005240778	SCV005887712	pathogenic	Familial hyperinsulinism	2025-01-21	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.96C>G (p.Asn32Lys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.96C>G has been reported in the literature in multiple bi-allelic individuals affected with Congenital Hyperinsulinism (examples: Kapoor_2013, Alaei_2016, Hashemian_2021) and at-least one heterozygous individual affected with Congenital Hyperinsulinism (examples: Razzaghy-Azar_2021). Additionally, it has also been reported in one compound heterozygous individual affected with MODY (Evin_2023). These data indicate that the variant is very likely to be associated with Congenital Hyperinsulinism. The following publications have been ascertained in the context of this evaluation (PMID: 28123437, 23345197, 34927408, 34055426, 37071846). ClinVar contains an entry for this variant (Variation ID: 2678076). While this variant has been reported in the literature, the clinical significance of the variant for Autosomal Dominant Congenital Hyperinsulinism could not be established. Based on the evidence outlined above, this variant is pathogenic for Autosomal Recessive Congenital Hyperinsulinism.