Submissions for variant NM_000352.6(ABCC8):c.2797C>T (p.Arg933Ter)

gnomAD frequency: 0.00003  dbSNP: rs570388861

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169216	SCV000220475	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2014-07-02	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000201910	SCV001198264	pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg933*) 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 (rs570388861, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with autosomal recessive hyperinsulinism (PMID: 16429405, 26740944, 27188453). This variant is also known as p.Arg934*. ClinVar contains an entry for this variant (Variation ID: 188864). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169216	SCV001361438	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2019-01-24	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.2797C>T (p.Arg933X) 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. The variant allele was found at a frequency of 1.4e-05 in 277126 control chromosomes (gnomAD). c.2797C>T has been reported in the literature in multiple homozygous and comopound heterozygote individuals affected with Congenital Hyperinsulinism (Wang_2017, Martinez_2016, Snider_2013). These data indicate that the variant is very likely to be associated with disease. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Johns Hopkins Genomics, Johns Hopkins University	RCV000201910	SCV001762355	likely pathogenic	not provided	2021-07-27	criteria provided, single submitter	clinical testing	ABCC8 c.2797C>T (rs570388861) is rare (<0.1%) in a large population dataset (gnomAD: 4/282772 total alleles; 0.0014%; no homozygotes) and has been reported in ClinVar (Variation ID: 188864). It has been reported in 2 individuals with congenital hyperinsulinism. This nonsense variant results in a premature stop codon in exon 23 of 39 likely leading to nonsense-mediated decay and lack of protein production. We consider ABCC8 c.2797C>T to be likely pathogenic.
GeneDx	RCV000201910	SCV002098176	pathogenic	not provided	2022-02-07	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: 25525159, 27188453, 24750227, 16429405, 26740944, 23275527, 18339976, 33822359)
Fulgent Genetics, Fulgent Genetics	RCV002492688	SCV002797860	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2022-04-14	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468837	SCV004194671	pathogenic	Type 2 diabetes mellitus	2024-03-03	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000201910	SCV000256802	pathogenic	not provided	2015-10-07	no assertion criteria provided	clinical testing