ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.4306C>T (p.Arg1436Ter) (rs193922402)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169593 SCV000221103 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2015-01-29 criteria provided, single submitter literature only
Fulgent Genetics,Fulgent Genetics RCV000763233 SCV000893866 likely pathogenic Permanent neonatal diabetes mellitus; Transient neonatal diabetes mellitus 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000169593 SCV001361437 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2019-07-29 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.4306C>T (p.Arg1436X) 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. In addition, the variant is located close to a canonical splice site and therefore could affect mRNA splicing. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 157474 control chromosomes (gnomAD). c.4306C>T has been reported in the literature, in homozygous- or compound heterozygous state, in multiple individuals affected with diffuse Congenital Hyperinsulinism (CHI) (e.g. Aynsley-Green_1998, Kapoor_2013, Snider_2013, Warncke_2016) and was also found in heterozygosity in patients affected with the focal form of the disease (Barthlen_2008, Bendix_2018) that is consistent with the genetic mechanism of focal CHI (Bendix_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Aynsley-Green_1998). Two other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.