Submissions for variant NM_000352.6(ABCC8):c.1792C>T (p.Arg598Ter)

gnomAD frequency: 0.00002  dbSNP: rs139328569

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000500331	SCV000592997	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2017-03-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001380990	SCV001579233	pathogenic	not provided	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg598*) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). This variant is present in population databases (rs139328569, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with congenital hyperinsulinism (PMID: 14692646, 25972930). ClinVar contains an entry for this variant (Variation ID: 434056). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics	RCV001380990	SCV001879520	pathogenic	not provided	2020-09-25	criteria provided, single submitter	clinical testing	This variant is expected to result in the loss of a functional protein. The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant was identified heterozygous or compound heterozygous in individuals with focal or diffuse congenital hyperinsulinism.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797741	SCV002041539	pathogenic	Familial hyperinsulinism	2021-11-18	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.1792C>T (p.Arg598X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251442 control chromosomes. c.1792C>T has been widely reported in the literature in individuals affected with focal and diffuse forms of Congenital Hyperinsulinism (example, Suchi_2003, Roio Liberatore_2015, Mohnike_2014, Sang_2014). These data indicate that the variant is likely to be associated with disease. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Molecular Genetics, Madras Diabetes Research Foundation	RCV000500331	SCV002318432	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496936	SCV002811737	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2022-04-06	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000500331	SCV004026553	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The Arg598Ter variant in ABCC8 has been reported in >10 individuals with congenital hyperinsulinism (PMID: 20685672, 32851339, 18796520, 15466080, 25972930, 16429405, 16882742, 25639667, 15562009, 25117148), and has been identified in 0.006% (1/16254) of African/African American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139328569). 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 (VariationID: 434056) as pathogenic by many submitters. Of the 11 affected individuals, at least 4 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the Arg598Ter variant is pathogenic (Variation ID: 434053; PMID: 18796520, 15466080, 16882742, 15562009, 25117148). In vitro functional studies provide some evidence that the Arg598Ter variant may slightly impact protein function (PMID: 15466080, 36339418). However, these types of assays may not accurately represent biological function. This nonsense variant leads to a premature termination codon at position 598, which is predicted to lead to a truncated or absent protein. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1, PM3_very-strong, PS3_moderate, PM2_supporting (Richards 2015).
GeneDx	RCV001380990	SCV004036901	pathogenic	not provided	2023-09-21	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 33300273, 25972930, 32670376, 16429405, 31589614, 25525159, 33502730, 36208030, 27188453, 14692646, 25117148, 25008049, 24434300)
Baylor Genetics	RCV003470626	SCV004191361	pathogenic	Type 2 diabetes mellitus	2024-03-09	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001829422	SCV002075772	pathogenic	Hereditary hyperinsulinism	2021-09-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535574	SCV004750201	pathogenic	ABCC8-related disorder	2024-01-11	no assertion criteria provided	clinical testing	The ABCC8 c.1792C>T variant is predicted to result in premature protein termination (p.Arg598*). This variant has been reported in the compound heterozygous state with a second ABCC8 variant in individuals with diffuse and focal congenital hyperinsulinism (CHI) (Suchi et al. 2003. PubMed ID: 14692646; Snider et al. 2013. PubMedID: 23275527; Mohnike et al. 2014. PubMed ID: 24401662; Xu et al. 2021. PubMed ID: 33502730). This variant has also been reported heterozygous and paternally inherited in individuals with CHI and/or hypoglycemia (De Vroede et al. 2004. PubMed ID: 15466080; Jahnavi et al. 2014. PubMedID: 25117148; Mohnike et al. 2014. PubMed ID: 24401662). One individual of those was found to have mosaic paternal uniparental disomy 11p and suggestive of Beckwith-Wiedemann syndrome (BWS)- spectrum hyperinsulinism (Tung et al. 2020. PubMed ID: 32670376). The majority of individuals were diagnosed with focal CHI. This variant has also been reported de novo in individuals with CHI (Sang et al. 2014. PubMed ID: 25008049; Xu et al. 2021. PubMed ID: 33502730). At PreventionGenetics, this variant has been detected in the heterozygous state in two individuals who received testing for CHI, one of which was compound heterozygous (Internal Data). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. Nonsense variants in ABCC8 are expected to be pathogenic. This variant is interpreted as pathogenic.