ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.1254_1284dup (p.Met429Ter)

gnomAD frequency: 0.00001  dbSNP: rs768951263
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000503807 SCV000592996 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2016-03-01 criteria provided, single submitter clinical testing
Invitae RCV001381025 SCV001579276 pathogenic not provided 2024-01-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met429*) in the ABCC8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCC8 are known to be pathogenic (PMID: 20685672, 23345197). This variant is present in population databases (rs768951263, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with autosomal recessive diffuse or paternally inherited focal hyperinsulinism (PMID: 25201519). ClinVar contains an entry for this variant (Variation ID: 434055). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002307525 SCV002600738 pathogenic Familial hyperinsulinism 2022-10-27 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.1254_1284dup31 (p.Met429X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251476 control chromosomes (gnomAD). c.1254_1284dup31 has been reported in the literature in multiple individuals affected with Congenital Hyperinsulinism (Banerjee_2011, Kapoor_2013, Snider_2013, Arya_2014, Demirbilek_2014). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: all three classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics RCV002490827 SCV002776617 pathogenic Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 2021-12-02 criteria provided, single submitter clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000503807 SCV004026566 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2023-08-16 criteria provided, single submitter curation The Met429Ter variant in ABCC8 has been reported in at least 5 individuals with congenital hyperinsulinism (PMID: 25201519, 23345197, 23275527), and has been identified in 0.004% (4/113754) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs768951263). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (VariationID: 434056) as pathogenic by Invitae, Genetic Services Laboratory (University of Chicago), Women's Health and Genetics/Laboratory Corporation of America (LabCorp), and Natera Inc. Of the 5 affected individuals, at least 1 was a compound heterozygote that carried a reported pathogenic variant in trans, which increases the likelihood that the Met429Ter variant is pathogenic (Variation ID: 370604; PMID: 23275527). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 429 and leads to a premature termination codon 1 amino acid downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the ABCC8 gene is an established disease mechanism in autosomal recessive hyperinsulinemic hypoglycemia. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PVS1, PM3, PM2_supporting (Richards 2015).
Baylor Genetics RCV003470625 SCV004199476 pathogenic Type 2 diabetes mellitus 2023-07-15 criteria provided, single submitter clinical testing
Natera, Inc. RCV001829421 SCV002078214 pathogenic Hereditary hyperinsulinism 2021-10-14 no assertion criteria provided clinical testing

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.