Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000723825 | SCV000230073 | pathogenic | not provided | 2014-06-13 | criteria provided, single submitter | clinical testing | |
| Counsyl | RCV000009667 | SCV000485103 | pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2016-02-19 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000009667 | SCV001339055 | pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2020-03-09 | criteria provided, single submitter | clinical testing | Variant summary: ABCC8 c.560T>A (p.Val187Asp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 235200 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ABCC8 causing Congenital Hyperinsulinism (0.00015 vs 0.0034), allowing no conclusion about variant significance. c.560T>A has been reported in the literature in multiple families affected with Congenital Hyperinsulinism (Otonkoski_1999, Henquin_2011). At least one publication has reported the variant to result in non-functional channel (Otonkoski_1999). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Broad Center for Mendelian Genomics, |
RCV000009667 | SCV004026577 | pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 2023-08-16 | criteria provided, single submitter | curation | The p.Val187Asp variant in ABCC8 has been reported in >10 individuals with hyperinsulinemic hypoglycemia (PMID: 10334322, 16380471, 12364426, 19475716), and has been identified in 0.2% (42/23698) of European (Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852672). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 9099) and has been interpreted as pathogenic by Counsyl, OMIM, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), and Eurofins NTD LLC (GA). Of the many affected individuals, at least 4 were compound heterozygotes that carried a reported pathogenic variant in trans, which increases the likelihood that the p.Val187Asp variant is pathogenic (PMID: 16380471). In vitro functional studies provide some evidence that the p.Val187Asp variant may slightly impact protein function (PMID: 10334322). However, these types of assays may not accurately represent biological function. 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, this variant meets criteria to be classified as pathogenic for autosomal recessive hyperinsulinemic hypoglycemia. ACMG/AMP Criteria applied: PM3_very_strong, PP3, PS3_supporting (Richards 2015). |
| Baylor Genetics | RCV003473071 | SCV004202148 | likely pathogenic | Type 2 diabetes mellitus | 2023-05-18 | criteria provided, single submitter | clinical testing | |
| OMIM | RCV000009667 | SCV000029885 | pathogenic | Hyperinsulinemic hypoglycemia, familial, 1 | 1999-02-01 | no assertion criteria provided | literature only |