ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.4432G>A (p.Gly1478Arg)

gnomAD frequency: 0.00001  dbSNP: rs72559715
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000503504 SCV000592979 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2016-07-21 criteria provided, single submitter clinical testing
Counsyl RCV000503504 SCV000797781 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2018-02-16 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000710389 SCV000840599 pathogenic not provided 2018-06-25 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000763232 SCV000893865 likely pathogenic Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV000710389 SCV001582811 pathogenic not provided 2023-08-09 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1478 of the ABCC8 protein (p.Gly1478Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant congenital hyperinsulinism and autosomal dominant ABCC8-related early onset diabetes (PMID: 19475716, 30098243, 30977832, 32928245). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 434045). 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.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital RCV001848864 SCV002104247 pathogenic Autosomal dominant hyperinsulinism due to SUR1 deficiency 2019-07-01 criteria provided, single submitter clinical testing This is a recurrent variant that has been previously reported in individuals with congenital hyperinsulinism, albeit with variable expressivity and incomplete penetrance (PMID: 18596924, 19475716, 8650576, 23275527, 24401662).There are reports of both familial transmission of this variant (PMID: 18596924) and a sporadic case where the p.Gly1478Arg change occurred de novo (PMID: 19475716). The p.Gly1478Arg change falls within the second nucleotide-binding domain (NBD2) where MgADP binds (UniProtKB - Q09428). This variant has been experimentally demonstrated to impair responsiveness to channel agonists such as diazoxide and MgADP (PMID: 18596924). This variant has not been observed in large population cohorts (absent from >282,800 alleles tested; GnomAD v2.1).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV003330733 SCV004039404 pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2023-08-25 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.4432G>A (p.Gly1478Arg) 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 was absent in 251454 control chromosomes (gnomAD). c.4432G>A has been reported in the literature in multiple individuals affected with Dominant CH (e.g. Nichols_1996, Pinney_2008, Sandal_2009, Kapoor_2013), including at least one case of de novo inheritance (Sandal_2009), and it has been shown to segregate with the disease phenotype within family members, although with incomplete penetrance (Pinney_2008). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and found the variant resulted in diminished channel response to MgADP and diazoxide (Pinney_2008). The following publications have been ascertained in the context of this evaluation (PMID: 23345197, 8650576, 18596924, 19475716). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV003470623 SCV004193216 pathogenic Type 2 diabetes mellitus 2023-08-29 criteria provided, single submitter clinical testing

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