Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV002514097 | SCV003440275 | uncertain significance | not provided | 2022-10-13 | criteria provided, single submitter | clinical testing | This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 511 of the ABCC8 protein (p.Leu511Pro). This variant is present in population databases (rs797045206, gnomAD 0.007%). This missense change has been observed in individual(s) with autosomal recessive congenital hyperinsulinism (PMID: 28442472). ClinVar contains an entry for this variant (Variation ID: 210069). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
| Broad Center for Mendelian Genomics, |
RCV000194750 | SCV004026562 | uncertain significance | Hyperinsulinemic hypoglycemia, familial, 1 | 2023-08-16 | criteria provided, single submitter | curation | The p.Leu511Pro variant in ABCC8 has been previously reported in 1 individual, with hyperinsulinemic hypoglycemia (PMID: 28442472), and has been seen in 0.006% (1/15422) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP: rs797045206). 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: 210069) and has been interpreted as likely pathogenic by Genetic Services Laboratory (University of Chicago). 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.Leu511Pro variant is uncertain. ACMG/AMP Criteria applied: PM2_supporting, PP3 (Richards 2015). |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003387795 | SCV004099545 | uncertain significance | not specified | 2023-09-06 | criteria provided, single submitter | clinical testing | Variant summary: ABCC8 c.1532T>C (p.Leu511Pro) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 3.2e-05 in 31388 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1532T>C has been reported in the literature in individuals affected with Familial Hyperinsulinism (Li_2017). 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. The following publication has been ascertained in the context of this evaluation (PMID: 28442472). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Genetic Services Laboratory, |
RCV000194750 | SCV000246289 | likely pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2014-06-11 | flagged submission | clinical testing |