Submissions for variant NM_000352.6(ABCC8):c.4136G>A (p.Arg1379His)

gnomAD frequency: 0.00001  dbSNP: rs193922401

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000710386	SCV000840596	likely pathogenic	not provided	2017-09-28	criteria provided, single submitter	clinical testing
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV001249023	SCV001422930	likely pathogenic	Monogenic diabetes	2020-01-22	criteria provided, single submitter	curation	The p.Arg1379His (sometimes called p.Arg1380His) variant in ABCC8 has been reported in 12 individuals with Monogenic Diabetes and segregated with disease in 5 affected relatives from 2 families (PMID: 22210575, 23093687, 27271189, 21989597, 19342262, 17446535, 17389331; DOI: 10.1016/j.clinph.2015.04.103). Data from large population studies is insufficient to assess the frequency of this variant. 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 likely pathogenic in ClinVar (Variation ID: 585346). 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.Arg1379Ser, and p.Arg1379Cys), have been reported in association with disease in the literature and ClinVar, supporting that a change at this position may not be tolerated (PMID: 18025464; Variation ID: 9105, 35614, 35615). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic. ACMG/AMP Criteria applied: PM5, PP1_Moderate, PP3, PS4_moderate (Richards 2015).
Genetic Services Laboratory, University of Chicago	RCV000710386	SCV002065924	likely pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ABCC8 gene demonstrated a sequence change, c.4136G>A, in exon 34 that results in an amino acid change, p.Arg1379His. The p.Arg1379His change affects a highly conserved amino acid residue located in a domain of the ABCC8 protein that is known to be functional. The p.Arg1379His substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been described in the gnomAD database with a frequency of 0.011% in the Ashkenazi Jewish subpopulation (dbSNP rs193922401). This sequence change has been previously described in multiple individual and affected family members with neonatal diabetes/monogenic diabetes (PMID: 17446535, 21989597, 24622368, 33300273, 29207974, 22210575, 23093687, 27271189, 19342262, 17446535, 17389331). Additionally, other missense changes at this same position (p. Arg1379Cys, p. Arg1379Pro, p.Arg1379Leu, p. Arg1379Ser) have been reported in individuals with ABCC8-related diabetes (PMID: 16885549, 24622368, 27681997, 24622368, 18025408). This sequence change is the likely cause of this individual's phenotype, however functional studies have not been performed to prove this conclusively.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307604	SCV002600570	pathogenic	Maturity onset diabetes mellitus in young	2022-10-19	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.4136G>A (p.Arg1379His) 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 allele was found at a frequency of 1.5e-05 in 201446 control chromosomes. c.4136G>A has been reported in the literature in multiple individuals affected with Neonatal Diabetes Mellitus/Maturity Onset Diabetes Of The Young in an autosomal dominant manner (example: Bowman_2012, Flannagan_2007 and Bonfanti_2021). These data indicate that the variant is very likely to be associated with disease. Additional variants at the same position have been associated with NDM/MODY and related conditions in ClinVar and HGMD (R1379C, R1379L, R1379P, R1379S). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004535759	SCV004117558	likely pathogenic	ABCC8-related disorder	2023-03-10	criteria provided, single submitter	clinical testing	The ABCC8 c.4136G>A variant is predicted to result in the amino acid substitution p.Arg1379His. This variant has been reported multiple times in individuals with neonatal diabetes (including, but not limited to Flanagan et al. 2007. PubMed ID: 17446535; Bowman et al. 2011. PubMed ID: 21989597; Riveline et al. 2011. PubMed ID: 22210575 ). Different variants that affect this same amino acid residue (p.Arg1379Leu, p.Arg1379Ser, and p.Arg1379Cys) have been reported in association with disease (Rafiq et al. 2008. PubMed ID: 18025408; Bennett et al. 2015. PubMed ID: 25555642; Babenko et al. 2006. PubMed ID: 16885549), suggesting the p.Arg1379 is a critical residue for typical protein function. This variant is interpreted as likely pathogenic.