Submissions for variant NM_000352.6(ABCC8):c.4613G>A (p.Arg1538Gln)

dbSNP: rs1564869850

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000710393	SCV000840605	pathogenic	not provided	2018-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000710393	SCV001795958	pathogenic	not provided	2023-12-20	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect: impaired ATP-sensitive K+ channel response mechanisms (PMID: 18596924); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also published as R1539Q; This variant is associated with the following publications: (PMID: 32928245, 28270372, 21674179, 18596924, 21422196)
Genetic Services Laboratory, University of Chicago	RCV000710393	SCV002069063	pathogenic	not provided	2020-04-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000710393	SCV002242614	pathogenic	not provided	2024-11-21	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 1538 of the ABCC8 protein (p.Arg1538Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital hyperinsulinism (PMID: 18596924, 21422196, 21674179, 28270372, 32928245). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is also known as R1539Q. ClinVar contains an entry for this variant (Variation ID: 585348). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
PreventionGenetics, part of Exact Sciences	RCV004527754	SCV004110072	likely pathogenic	ABCC8-related disorder	2023-08-09	criteria provided, single submitter	clinical testing	The ABCC8 c.4613G>A variant is predicted to result in the amino acid substitution p.Arg1538Gln. Of note, this variant is also known as p.Arg1539Gln with NM_001287174.2. This variant has been reported in multiple individuals with infantile hyperinsulinism and hypoglycemia (See for example, Figure 1, Kapoor et al. 2011. PubMed ID: 21674179; Figure1, Pinney et al. 2008. PubMed ID: 18596924; Table 1, Casertano et al. 2020. PubMed ID: 32928245). In one family this variant was observed to segregate in five affected individuals with hypoglycemia and diabetes, but there was also one asymptomatic carrier individual as well (Kapoor et al. 2011. PubMed ID: 21674179). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as likely pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000710393	SCV005051602	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	ABCC8: PP1:Strong, PM1, PM2, PS2:Moderate, PS4:Moderate, PP3, PS3:Supporting
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV004556818	SCV002512152	uncertain risk allele	Neonatal diabetes mellitus	2024-05-27	flagged submission	research	This variant is found to be a potent moderate impact, variant with a CADD score of 32 and sufficient scientific evidence of gene-disease correlation. However, since this is not a high impact variant and no variant evidence, this variant is reclassified as Uncertain risk allele.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002245621	SCV002512153	uncertain risk allele	Maturity onset diabetes mellitus in young	2024-05-27	flagged submission	research	This variant is found to be a potent moderate impact, deleterious variant with a CADD score of 32 and sufficient scientific evidence to support gene-disease correlation. However, since this is not a high impact variant and has no variant evidence, this variant is reclassified as Uncertain Risk Allele