Submissions for variant NM_000352.6(ABCC8):c.4478G>A (p.Arg1493Gln)

gnomAD frequency: 0.00001  dbSNP: rs746480424

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000411593	SCV000486340	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2016-05-17	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001383606	SCV001582810	pathogenic	not provided	2024-01-09	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 1493 of the ABCC8 protein (p.Arg1493Gln). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with congenital autosomal recessive hyperinsulinism (PMID: 10426386, 12199344, 21968111, 25008049). This variant is also known as R1494Q. ClinVar contains an entry for this variant (Variation ID: 370910). 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%. This variant disrupts the p.Arg1493 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9769320, 15579781, 30186238). 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.
GeneDx	RCV001383606	SCV002072837	likely pathogenic	not provided	2021-12-23	criteria provided, single submitter	clinical testing	Identified in multiple other unrelated patients with hyperinsulinism in the published literature, often inherited on the paternal allele; somatic 11p maternal allele studies were not performed (Sang et al., 2014; Gong et al., 2015); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Occasionally reported as R1494Q using alternate nomenclature; This variant is associated with the following publications: (PMID: 14692646, 23275527, 21968111, 12199344, 20799350, 23226049, 20685672, 25639667, 10426386, 25008049)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000411593	SCV004026536	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Arg1493Gln variant in ABCC8 has been reported in 8 individuals with hyperinsulinemic hypoglycemia (PMID: 20685672, 12199344, 25639667, 21968111, 34304300, 25008049, 23275527, 10426386), and has been identified in 0.0008% (1/129096) of European (Non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs746480424). 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#: 370910) and has been interpreted as pathogenic by Invitae and likely pathogenic by Counsyl and GeneDx. Of the 8 affected individuals, at least 2 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg1493Gln variant is pathogenic (PMID: 10426386, 25008049). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. One additional pathogenic variant, resulting in a different amino acid change at the same position, p.Arg1493Trp has been reported in association with disease in ClinVar and the literature, supporting that a change at this position may not be tolerated (Variation ID: 9096, PMID: 30186238, 33688939, 10202168, 10426386, 19475716, 9769320, 15579781). 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: PM3_strong, PM5, PP3, PP2_supporting (Richards 2015).
Baylor Genetics	RCV003470337	SCV004191161	likely pathogenic	Type 2 diabetes mellitus	2024-03-25	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000411593	SCV005399589	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with congenital hyperinsulism (CHI) and neonatal diabetes mellitus (NDM), respectively (PMIDs: 32376986, 32027066). (I) 0108 - This gene is known to be associated with both recessive and dominant disease. The ABCC8 gene has been associated with both autosomal recessive and dominant NDM and CHI (PMID: 32027066). Focal CHI is caused by a somatic second hit with the loss of the maternal chromosome 11p15.5 region by uniparental disomy that makes the paternally inherited variant mosaic homozygous (PMID: 32027066). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variable penetrance has been reported for hyperinsulinemic hypoglycaemia, familial, 1 (MIM#256450) (PMID: 20301549). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (1 heterozygote, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) (highest allele count: 4 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated ABC transporter domain (DECIPHER). (I) 0702 - Other missense variants comparable to the one identified in this case have strong previous evidence for pathogenicity. p.(Arg1493Pro), p.(Arg1493Trp) and p.(Arg1493Leu) have been classified as likely pathogenic or pathogenic by clinical laboratories in ClinVar. p.(Arg1493Trp) has also been observed in an individual with focal CHI in the literature (PMID: 20685672). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic and likely pathogenic by clinical laboratories in ClinVar, and has been observed as paternally inherited in several individuals with CHI in the literature (PMIDs: 10426386, 33502730, 20685672). This includes one individual with focal CHI where the variant was homozygous in focal lesion tissue due to uniparental disomy and the somatic loss of maternal 11p15 (PMID: 10426386). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign