Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV002004428 | SCV002293263 | likely pathogenic | not provided | 2025-01-13 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1515 of the ABCC8 protein (p.Thr1515Met). This variant is present in population databases (rs769989185, gnomAD 0.0009%). This missense change has been observed in individuals with autosomal dominant ABCC8-related early onset diabetes and/or familial hyperinsulinism (PMID: 21378087, 27908292, 33013711; internal data). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Thr1516Met. ClinVar contains an entry for this variant (Variation ID: 1506182). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| MGZ Medical Genetics Center | RCV002290835 | SCV002580676 | likely pathogenic | Type 2 diabetes mellitus | 2022-01-21 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV004699641 | SCV005204853 | pathogenic | Maturity onset diabetes mellitus in young | 2024-06-10 | criteria provided, single submitter | clinical testing | Variant summary: ABCC8 c.4544C>T (p.Thr1515Met) 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. In addition, this variant disrupts the penultimate nucleotide of exon 37, and therefore can affect splicing. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site. One predict the variant strengthens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251076 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4544C>T has been reported in the literature in at least one heterozygous individual with congenital hyperinsulinism where the variant was matrnally inherited (e.g., Banerjee_2011) and in several heterozygous individuals affected with Maturity Onset Diabetes Of The Young, where the variant was found to segregate with disease in at least one family (e.g., Lin_2020, Sampathkumar_2022). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21378087, 33013711, 34741762). ClinVar contains an entry for this variant (Variation ID: 1506182). Based on the evidence outlined above, the variant was classified as pathogenic. |
| Gene |
RCV002004428 | SCV005325033 | likely pathogenic | not provided | 2024-02-21 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34014594, 21378087, 33013711, 34741762) |
| Fulgent Genetics, |
RCV005042680 | SCV005676652 | pathogenic | Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3 | 2024-06-14 | criteria provided, single submitter | clinical testing |