Submissions for variant NM_000352.6(ABCC8):c.2857C>T (p.Gln953Ter)

gnomAD frequency: 0.00001  dbSNP: rs541269678

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169265	SCV000220556	likely pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2014-07-25	criteria provided, single submitter	literature only
Genetic Services Laboratory, University of Chicago	RCV000169265	SCV000592992	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2015-12-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780808	SCV000918370	likely pathogenic	Familial hyperinsulinism	2018-05-14	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.2857C>T (p.Gln953X) 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 (e.g., p.Arg998X and p.Asp1192fsX16). The variant allele was found at a frequency of 1.6e-05 in 246868 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (1.6e-05 vs 3.40e-03), allowing no conclusion about variant significance. The variant, c.2857C>T, has been reported in the literature in multiple individuals affected with Familial Hyperinsulinism (Nestorowicz_1998, Bellanne-Chantelot_2010, Arya_2014, Snider_2013, Valin_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV001040693	SCV001204282	pathogenic	not provided	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln953*) 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 (rs541269678, gnomAD 0.004%). This premature translational stop signal has been observed in individuals with congenital hyperinsulinism (PMID: 9618169, 23275527, 23506826, 28442472). This variant is also known as p.Gln954*in the literature. ClinVar contains an entry for this variant (Variation ID: 188905). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000169265	SCV002038582	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2021-06-11	criteria provided, single submitter	clinical testing	The ABCC8 c.2860C>T (p.Gln954Ter) variant is stop-gained variant that is predicted to result in a premature termination or absence of the protein. Across a selection of the available literature, the p.Gln954Ter variant has been reported in at least two individuals with paternally-inherited, monoallelic hyperinsulinemic hypoglycemia and in five individuals with autosomal recessive hyperinsulinemic hypoglycemia (Nestorowicz et al. 1998; Snider et al. 2013; Arya et al. 2014; Li et al. 2017). The p.Gln954Ter variant is reported in at a frequency of 0.00003516 in the European (non-Finnish) population of Genome Aggregation Database version 2.1.1. Based on the collective evidence, the p.Gln954Ter variant is classified as pathogenic for hyperinsulinemic hypoglycemia.
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000169265	SCV002762749	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2022-08-25	criteria provided, single submitter	research	ACMG codes:PVS1, PS4M, PM2
Fulgent Genetics, Fulgent Genetics	RCV002505223	SCV002809635	pathogenic	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2022-04-16	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV003447512	SCV004175338	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2021-08-18	criteria provided, single submitter	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV001040693	SCV002036399	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001040693	SCV002037319	likely pathogenic	not provided		no assertion criteria provided	clinical testing