Submissions for variant NM_000352.6(ABCC8):c.4178G>A (p.Arg1393His)

gnomAD frequency: 0.00003  dbSNP: rs769279368

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	RCV000518373	SCV000612218	likely pathogenic	not provided	2017-06-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000671471	SCV002060360	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2021-11-10	criteria provided, single submitter	clinical testing	NM_000352.3(ABCC8):c.4178G>A(R1393H) is a missense variant classified as a variant of uncertain significance in the context of familial hyperinsulinism, ABCC8-related. R1393H has been observed in cases with relevant disease (PMID: 9618169). Functional assessments of this variant are available in the literature (PMID: 9648840, 11457841). R1393H has been observed in population frequency databases (gnomAD: SAS 0.01%). In summary, there is insufficient evidence to classify NM_000352.3(ABCC8):c.4178G>A(R1393H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Genetic Services Laboratory, University of Chicago	RCV000518373	SCV002069098	likely pathogenic	not provided	2018-02-06	criteria provided, single submitter	clinical testing
Invitae	RCV000518373	SCV003439796	uncertain significance	not provided	2022-02-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1393 of the ABCC8 protein (p.Arg1393His). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with clinical features of autosomal recessive congenital hyperinsulinism (PMID: 9618169). This variant is also known as R1394H. ClinVar contains an entry for this variant (Variation ID: 446776). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on ABCC8 function (PMID: 9648840, 11457841, 17575084). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx	RCV000518373	SCV003924897	likely pathogenic	not provided	2022-11-12	criteria provided, single submitter	clinical testing	Reported in a patient with familial hyperinsulinism who also harbors an additional variant in the ABCC8 gene (Nestorowicz et al., 1998); Also known as p.R1394H (c.4181G>A); Published functional studies using transfected cells were not consistent in their results regarding the potential effect of this variant on channel function and protein trafficking (Shyng et al., 1998; Partridge et al., 2001; Yan et al., 2004); 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: 9648840, 17575084, 32041611, 11457841, 17956278, 24399968, 14707124, 9618169, 23226049)
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000671471	SCV004026509	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Arg1393His variant in ABCC8 has been reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 9648840, 9618169, 32041611) and has been identified in 0.008% (2/25832) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs769279368). 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: 446776) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago), Natera Inc., and Athena Diagnostics Inc., and as a variant of uncertain significance by Myriad Women's Health Inc. and Counsyl. Of the 2 affected individuals, 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Arg1393His variant is pathogenic (Variation ID: 9088; PMID: 9648840). In vitro functional studies provide some evidence that the p.Arg1393His variant may impact protein function (PMID: 9648840, 11457841). 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, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PM3, PP3, PM2_supporting, PS3_supporting (Richards 2015).
Baylor Genetics	RCV003470643	SCV004197321	likely pathogenic	Type 2 diabetes mellitus	2023-10-17	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001277180	SCV001464078	likely pathogenic	Hereditary hyperinsulinism	2020-09-16	no assertion criteria provided	clinical testing
Diabetes Institute, Department of Endocrinology and Metabolism, First Affiliated Hospital of Zhengzhou University	RCV003884589	SCV004698202	pathogenic	Maturity onset diabetes mellitus in young		no assertion criteria provided	clinical testing