Submissions for variant NM_000352.6(ABCC8):c.4135C>A (p.Arg1379Ser)

gnomAD frequency: 0.00001  dbSNP: rs137852673

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029261	SCV000051907	uncertain significance	not specified	2019-01-15	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.4135C>A (p.Arg1379Ser) results in a non-conservative amino acid change located in the ABC transporter-like and AAA+ ATPase domains 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 205110 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4135C>A, has been reported in the literature in at-least one individual affected with Neonatal Diabetes Mellitus (Bennett_2015) and was also observed in a patient undergoing testing for Neonatal diabetes mellitus in our laboratory (2011) who is lost to follow-up. Therefore, these data do not allow any firm conclusions about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant affecting the same codon, c.4135C>T (p.Arg1379Cys), has been reported by Babenko et al (2006) and classified as pathogenic in our laboratory and in external databases (example ClinVar), suggesting this is a functionally important codon. 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 uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Counsyl	RCV000675131	SCV000800706	uncertain significance	Hyperinsulinemic hypoglycemia, familial, 1	2018-05-09	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001248973	SCV001422805	uncertain significance	Monogenic diabetes	2020-01-22	criteria provided, single submitter	curation	The p.Arg1379Ser (sometimes called p.Arg1380Ser) variant in ABCC8 has been reported in 1 individual with Monogenic Diabetes (PMID: 25555642), and has been identified in 0.009857% (3/30434) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs137852673). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a carrier frequency. Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported as a VUS and as a likely pathogenic variant in ClinVar (Variation ID: 35614). Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Three additional variants, each with a different amino acid change at the same position, (p.Arg1379Leu, p.Arg1379His, and p.Arg1379Cys), have been reported in association with disease in ClinVar or curated as a likely pathogenic variant or variant of uncertain significance by our study, supporting that a change at this position may not be tolerated (Variation ID: 35615). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PM2_Supporting, PP3 (Richards 2015).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001852582	SCV002244497	uncertain significance	not provided	2024-03-04	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 1379 of the ABCC8 protein (p.Arg1379Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with autosomal neonatal diabetes mellitus (PMID: 25555642). ClinVar contains an entry for this variant (Variation ID: 35614). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg1379 amino acid residue in ABCC8. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16885549, 17446535, 18025464, 27681997). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Fulgent Genetics, Fulgent Genetics	RCV005042087	SCV005683379	uncertain significance	Diabetes mellitus, transient neonatal, 2; Hyperinsulinemic hypoglycemia, familial, 1; Leucine-induced hypoglycemia; Type 2 diabetes mellitus; Diabetes mellitus, permanent neonatal 3	2024-06-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001835635	SCV002077516	uncertain significance	Hereditary hyperinsulinism	2020-04-07	no assertion criteria provided	clinical testing