ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.76T>A (p.Cys26Ser)

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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 RCV001817862 SCV002067268 pathogenic not provided 2019-02-26 criteria provided, single submitter clinical testing DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.76T>A, in exon 1 that results in an amino acid change, p.Cys26Ser. This pathogenic sequence change has previously been described in the compound heterozygous state a patient with ABCC8-related hyperinsulinemic hypoglycemia (PMID: 21199866). Fukada et al. found that the p.Cys26 position is high conserved in ABC transporters due to Cys-Cys bonds that occur within these transporter proteins. In vitro analysis of the p.Cys26Ser change showed that it affected SUR1 maturation (i.e. full glycosylation) by interfering with the formation of a Cys-Cys bond between p.Cys6 and p.Cys26 (PMID: 21199866). The p.Cys26Ser change affects a highly conserved amino acid residue located in a domain of the SUR1 protein that is known to be functional. The p.Cys26Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL)." DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.76T>A, in exon 1 that results in an amino acid change, p.Cys26Ser. This pathogenic sequence change has previously been described in the compound heterozygous state a patient with ABCC8-related hyperinsulinemic hypoglycemia (PMID: 21199866). Fukada et al. found that the p.Cys26 position is high conserved in ABC transporters due to Cys-Cys bonds that occur within these transporter proteins. In vitro analysis of the p.Cys26Ser change showed that it affected SUR1 maturation (i.e. full glycosylation) by interfering with the formation of a Cys-Cys bond between p.Cys6 and p.Cys26 (PMID: 21199866). The p.Cys26Ser change affects a highly conserved amino acid residue located in a domain of the SUR1 protein that is known to be functional. The p.Cys26Ser substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, CADD, REVEL).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001844417 SCV002103457 likely pathogenic Familial hyperinsulinism 2022-02-17 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.76T>A (p.Cys26Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 244362 control chromosomes. c.76T>A has been reported in the literature in at least one individual affected with hyperinsulinemic hypoglycemia (Fukuda_2011). At least one publication reports experimental evidence evaluating an impact on protein function and showed that C26S led to instability and ER retention (Fukuda_2011, Wang_2012). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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