ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs541269678
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Total submissions: 7
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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 2021-08-31 criteria provided, single submitter clinical testing
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.
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

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