Submissions for variant NM_000352.6(ABCC8):c.19G>C (p.Gly7Arg)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003058290	SCV003439711	likely pathogenic	not provided	2023-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 7 of the ABCC8 protein (p.Gly7Arg). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individuals with autosomal recessive diffuse or focal hyperinsulinism (PMID: 16357843, 23275527). ClinVar contains an entry for this variant (Variation ID: 2137020). 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%. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 17575084, 23744072). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003317639	SCV004020577	likely pathogenic	Familial hyperinsulinism	2023-06-30	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.19G>C (p.Gly7Arg) 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 variant allele was found at a frequency of 5e-06 in 198218 control chromosomes. c.19G>C has been reported in both the homozygous and heterozygous state in the literature in individuals affected with ABCC8-related conditions (e.g., Suchi_2006, Snider_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating that the variant reduces cell surface expression which indicates a trafficking defect. The most pronounced variant effect results in 30%-50% of normal activity (Yan_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17575084, 23275527, 16357843). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003321969	SCV004026596	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Gly7Arg variant in ABCC8 has been reported in at least one affected individual, in the compound heterozygous state, with hyperinsulinemic hypoglycemia (PMID: 16357843, 17575084), and has been identified in 0.0034% (1/29138) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs781059815). 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. In vitro functional studies provide some evidence that the p.Gly7Arg variant impacts protein trafficking to the cell surface (PMID: 16357843, 23744072). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. 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: PS3_Supporting, PM2, PM3, PP3 (Richards 2015).
PreventionGenetics, part of Exact Sciences	RCV004529198	SCV004106406	likely pathogenic	ABCC8-related disorder	2023-08-07	criteria provided, single submitter	clinical testing	The ABCC8 c.19G>C variant is predicted to result in the amino acid substitution p.Gly7Arg. This variant has been reported in multiple individuals with both focal and diffuse forms of congenital hyperinsulinism and in at least one individual with focal form a loss of the maternal allele was noted (Suchi et al. 2006. PubMed ID: 16357843; Supplemental Appendix, Snider et al. 2012. PubMed ID: 23275527). Functional studies found this variant results in defective trafficking (Yan et al. 2007. PubMed ID: 17575084). This variant is reported in 0.0034% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-17498305-C-G). This variant is interpreted as likely pathogenic.