ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.1183A>T (p.Ile395Phe)

gnomAD frequency: 0.00001  dbSNP: rs542947894
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV001817637 SCV002072152 uncertain significance not specified 2017-08-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002545178 SCV003439583 pathogenic not provided 2024-01-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 395 of the ABCC8 protein (p.Ile395Phe). This variant is present in population databases (rs542947894, gnomAD 0.01%). This missense change has been observed in individual(s) with autosomal dominant diabetes mellitus (PMID: 32792356). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1338266). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001817637 SCV003934475 uncertain significance not specified 2023-05-17 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.1183A>T (p.Ile395Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251478 control chromosomes. c.1183A>T has been reported in the literature as a de-novo occurrence in at-least one heterozygous individual affected with neonatal diabetes mellitus (NDM) and as a VUS in another individual with NDM (examples: Lin_2020, DeFranco_2020). It has also been reported as a presumed compound heterozygote (phase not specified) in an individual with diffuse congenital hyperinsulinism who inherited this variant on the maternal allele along with a de-novo ABCC8 variant (Skimic_2020). As inheritance of two recessively acting or one dominant acting ABCC8 mutation can result in diffuse disease, these data indicate that the variant may be 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: 32027066, 32418263, 32792356, 33193079). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic citing one but not all evidence utilized in the context of this evaluation and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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