Submissions for variant NM_000352.6(ABCC8):c.221G>A (p.Arg74Gln)

gnomAD frequency: 0.00001  dbSNP: rs72559734

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586584	SCV000696585	pathogenic	Familial hyperinsulinism	2017-07-27	criteria provided, single submitter	clinical testing	Variant summary: The ABCC8 c.221G>A (p.Arg74Gln) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found at a low frequency in the control population (1/121894 control chromosomes). The variant was reported in the literature in multiple patients with congenital hyperinsulinemia (CHI) both in the homozgous and compound heterozygous states. Taken together, this variant is classified as pathogenic.
Athena Diagnostics	RCV000710375	SCV000840585	pathogenic	not provided	2022-07-15	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with congenital hyperinsulinism. This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls. Computational tools predict that this variant is damaging.
Fulgent Genetics, Fulgent Genetics	RCV000763236	SCV000893869	pathogenic	Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000710375	SCV001389945	pathogenic	not provided	2024-02-14	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 74 of the ABCC8 protein (p.Arg74Gln). This variant is present in population databases (rs72559734, gnomAD 0.003%). This missense change has been observed in individual(s) with autosomal recessive familial hyperinsulinism (PMID: 21992908, 23345197). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 495834). 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 80%. This variant disrupts the p.Arg74 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14692646, 16429405, 24645945, 25518065). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000710375	SCV002069196	pathogenic	not provided	2018-05-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000710375	SCV002574367	pathogenic	not provided	2022-03-17	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33046911, 30352420, 9618169, 27810688, 23275527, 20685672, 21992908, 23345197)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000984140	SCV004026585	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Arg74Gln variant in ABCC8 has been reported in >10 individuals with hyperinsulinemic hypoglycemia (PMID: 9618169, 10338089, 10828824, 20685672, 23275527, 23345197, 28701683, 30352420, 36239000), and has been identified in 0.003% (1/30616) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72559734). 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: 495834) and has been interpreted as pathogenic by multiple sources. Of the many affected individuals, at least 5 were compound heterozygotes that carried a reported pathogenic variant in trans, and at least 1 was a homozygote, which increases the likelihood that the p.Arg74Gln variant is pathogenic (Variation ID: 9088, 188915, 210074, 188931; PMID: 23275527, 23345197, 30352420, 36239000). 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, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very_strong, PM2_supporting, PP3 (Richards 2015).
Baylor Genetics	RCV003459457	SCV004199008	pathogenic	Type 2 diabetes mellitus	2023-06-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005044870	SCV005676122	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-04-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000984140	SCV001132111	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2019-02-26	no assertion criteria provided	clinical testing