Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Genetic Services Laboratory, |
RCV001817954 | SCV002067480 | uncertain significance | not specified | 2020-08-31 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001817954 | SCV002600571 | uncertain significance | not specified | 2022-10-19 | criteria provided, single submitter | clinical testing | Variant summary: ABCC8 c.2389C>T (p.Arg797Trp) results in a non-conservative amino acid change located in the ABC transporter-like, ATP-binding domain (IPR003439) of 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 4.8e-05 in 251480 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ABCC8 causing Familial Hyperinsulinism (4.8e-05 vs 0.0034), allowing no conclusion about variant significance. c.2389C>T has been reported in the literature in an individual affected with Hyperinsulinism without strong evidence for causality (Snider_2013). This report does not provide unequivocal conclusions about association of the variant with Familial Hyperinsulinism. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Broad Center for Mendelian Genomics, |
RCV003321877 | SCV004026541 | uncertain significance | Hyperinsulinemic hypoglycemia, familial, 1 | 2023-08-16 | criteria provided, single submitter | curation | The p.Arg797Trp variant in ABCC8 has been previously reported in 1 individual, in the compound heterozygous state, with hyperinsulinemic hypoglycemia (PMID: 23275527) and has been seen in 0.02% (3/19954) of East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs142620721). 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 (Variation ID: 1338583) and has been interpreted as a variant of uncertain significance by Genetic Services Laboratory (University of Chicago) and Women's Health and Genetics/Laboratory Corporation of America (LabCorp). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Arg836Gln variant is uncertain. ACMG/AMP Criteria applied: PP3, PM2_supporting, PM3 (Richards 2015). |