ClinVar Miner

Submissions for variant NM_000352.4(ABCC8):c.2857C>T (p.Gln953Ter) (rs541269678)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169265 SCV000220556 likely pathogenic Persistent hyperinsulinemic hypoglycemia of infancy 2014-07-25 criteria provided, single submitter literature only
Genetic Services Laboratory, University of Chicago RCV000169265 SCV000592992 pathogenic Persistent hyperinsulinemic hypoglycemia of infancy 2015-12-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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