ClinVar Miner

Submissions for variant NM_000207.3(INS):c.-152C>A

dbSNP: rs748749585
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001569335 SCV001793392 pathogenic not provided 2023-04-05 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on INS promoter activity (Garin et al., 2010); Also referred to as c.-331C>A using alternate nomenclature; This variant is associated with the following publications: (PMID: 20301620, 20133622, 21592955, 20938745, 32656923, 34426871, 21808142, 33409956, 25755231)
Genetic Services Laboratory, University of Chicago RCV001569335 SCV002067469 likely pathogenic not provided 2020-07-22 criteria provided, single submitter clinical testing DNA sequence analysis of the INS gene demonstrated a heterozygous sequence change in the 5’untranslated region, c.-152C>A. Garin et al., 2010, identified this sequence change (referred to as c.-331C>A) in the homozygous state in two unrelated individuals with transient neonatal diabetes (PMID 20133622). Interestingly, the carrier parents had normal glucose tolerance indicating that this single insulin allele is sufficient to provide the insulin required to maintain normal glycaemia. Functional studies demonstrated that this variant significantly impaired INS transcription in vitro (PMID 20133622). This sequence change is present at a low frequency of 0.0096% in the gnomAD population database (dbSNP rs748749585).
Fulgent Genetics, Fulgent Genetics RCV005044743 SCV005676235 pathogenic Type 1 diabetes mellitus 2; Maturity-onset diabetes of the young type 10; Hyperproinsulinemia; Diabetes mellitus, permanent neonatal 4 2024-03-19 criteria provided, single submitter clinical testing
GeneReviews RCV000055787 SCV000086753 not provided Permanent neonatal diabetes mellitus no assertion provided literature only
PreventionGenetics, part of Exact Sciences RCV003419839 SCV004108145 pathogenic INS-related disorder 2024-02-27 no assertion criteria provided clinical testing The INS c.-152C>A variant is located in the 5' untranslated region. This variant has been reported as a recessive, pathogenic allele for neonatal diabetes in two families due to insulin biosynthesis impairment (reported as c.-331C>A at Garin et al. 2010. PubMed ID: 20133622; Støy et al. 2010. PubMed ID: 20938745). Of note, heterozygous carrier parents in Garin et al. study were reported to be unaffected with neonatal diabetes. Moreover, another study showed that a different substitution at the same nucleotide position c.-152C>G occurs at a binding site of Kruppel-like transcription factor (KLF); this change causes a failure of binding Kruppel-like transcription factor 11 (KLF11) and hence inhibits KLF11-mediated INS activation (reported as c.-331C>G at Bonnefond et al. 2011. PubMed ID: 21592955). This variant is reported in 0.023% of alleles in individuals of African descent in gnomAD. This variant is interpreted as pathogenic.

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