Submissions for variant NM_000352.6(ABCC8):c.2693G>A (p.Trp898Ter)

dbSNP: rs1382448285

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780809	SCV000918371	likely pathogenic	Familial hyperinsulinism	2022-03-26	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.2693G>A (p.Trp898X) 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 4e-06 in 251324 control chromosomes. c.2693G>A has been reported in the literature in individuals affected with Focal and Congenital forms of Hyperinsulinism (example, Snider_2013, Jahnavi_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV001280725	SCV001468039	likely pathogenic	not provided	2020-08-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001280725	SCV003439578	pathogenic	not provided	2022-09-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp898*) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with autosomal recessive familial hyperinsulinism (PMID: 23275527, 25117148). This variant is also known as c.2696G>A, p.Trp899*. ClinVar contains an entry for this variant (Variation ID: 633028). For these reasons, this variant has been classified as Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003321734	SCV004026539	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Trp898Ter variant in ABCC8 has been reported in 2 individuals with hyperinsulinemic hypoglycemia (PMID: 25117148, 23275527), and has been identified in 0.0009% (1/113606) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs1382448285). 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: 633028) and has been interpreted as likely pathogenic by Greenwood Genetic Center Diagnostic Laboratories (Greenwood Genetic Center), Women's Health and Genetics/Laboratory Corporation of America (LabCorp), and Natera (Inc.). Of the 2 affected individuals, one of those was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Trp898Ter variant is pathogenic (PMID: 23275527). This nonsense variant leads to a premature termination codon at position 898, 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, PM2_supporting, PM3 (Richards 2015).
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV004545800	SCV004046430	pathogenic	ABCC8-related disorder		criteria provided, single submitter	clinical testing	This nonsense variant found in exon 23 of 39 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a compound heterozygous change in a patient with severe congenital hyperinsulinemic hypoglycemia (PMID: 25117148). The c.2693G>A (p.Trp898Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/251324) and is absent in the homozygous state, thus is presumed to be rare. Based on the available evidence, the c.2693G>A (p.Trp898Ter) variant is classified as Pathogenic.
Baylor Genetics	RCV003467313	SCV004200131	pathogenic	Type 2 diabetes mellitus	2023-12-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005047042	SCV005676327	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-03-07	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001830672	SCV002075671	likely pathogenic	Hereditary hyperinsulinism	2021-07-28	no assertion criteria provided	clinical testing