ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.4153T>C (p.Ser1385Pro)

dbSNP: rs2133402479
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001817985 SCV002069644 likely pathogenic not provided 2021-02-03 criteria provided, single submitter clinical testing The p.Ser1385Pro change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. The p.Ser1385Pro substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been described in the literature in a patient with diazoxide-responsive persistent hyperinsulinemic hypoglycemia and asymptomatic diffuse cardiac hypertrophy in a de novo state (PMID: 17597441). This sequence change is absent from the large population databases such as ExAC and gnomAD (dbSNP NA).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003388053 SCV004100133 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2023-09-26 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.4153T>C (p.Ser1385Pro) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 211408 control chromosomes (gnomAD). c.4153T>C has been reported in the literature in at least two individuals affected with Dominant Congenital Hyperinsulinism, one of which was a de novo occurrence (e.g. Natarajan_2007, Pinney_2008). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17597441, 18596924). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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