Submissions for variant NM_000352.6(ABCC8):c.4307G>A (p.Arg1436Gln)

dbSNP: rs387906407

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001040039	SCV001203594	pathogenic	not provided	2024-02-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1436 of the ABCC8 protein (p.Arg1436Gln). This variant also falls at the last nucleotide of exon 35, which is part of the consensus splice site for this exon. This variant is present in population databases (rs387906407, gnomAD 0.007%). This missense change has been observed in individuals with autosomal recessive diffuse or focal ABCC8-related conditions (PMID: 23275527, 26431509). This variant is also known as R1437Q. ClinVar contains an entry for this variant (Variation ID: 9086). 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. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 10615958, 17466004). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001260357	SCV001437302	pathogenic	Familial hyperinsulinism	2020-09-18	criteria provided, single submitter	clinical testing	Variant summary: ABCC8 c.4307G>A (p.Arg1436Gln) results in a conservative amino acid change located in the AAA+ ATPase domain (IPR003593) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant is also located to the last nucleotide of exon 35, therefore might affect splicing. Several computational tools predict a significant impact on normal splicing: one predicts the variant abolishes a 5' splicing donor site, while three predict the variant weakens this 5' donor site. At least one publication reported experimental evidence and confirmed that this variant affects mRNA splicing (Thomas_1995). The variant was absent in 157474 control chromosomes (gnomAD). c.4307G>A has been reported in the literature in multiple homozygous-, compound heterozygous- and heterozygous individuals affected with Congenital Hyperinsulinism, and in several of the reported families the was variant noted to co-segregate with the disease (e.g. Thomas_1995, Dunne_1997, Nestorowicz_1998, Tanizawa_2000, Fernandez_2006, Greer_2007, Muzyamba_2007, Rozenkova_2015, Warncke_2016). These data indicate that the variant is very likely to be associated with the disease. A publication demonstrated the absence of activity of ATP-dependent potassium channels when examining pancreatic beta cells derived from a homozygous patient (Dunne_1997); in addition, other reports evaluating the protein level impact of the variant using (intronless) cDNA constructs, demonstrated an almost complete lack of channel activity for the variant protein (Tanizawa_2000, Muzyamba_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Genetic Services Laboratory, University of Chicago	RCV001040039	SCV002069174	pathogenic	not provided	2018-04-27	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001040039	SCV002817264	pathogenic	not provided	2021-03-26	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple individuals with clinical features associated with this gene (PMID: 27682711, 26431509, 10615958, 9618169, 7716548, 12199344, 16186397, 18493152, 9365062). This variant is located in a region that is considered important and the assessment of experimental evidence suggests that this variant results in abnormal protein function (PMID: 10615958, 17466004). Computational tools yielded predictions that this variant may interfere with normal RNA splicing, which is supported by experimental evidence (PMID 7716548).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000009654	SCV004026506	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2023-08-16	criteria provided, single submitter	curation	The p.Arg1436Gln variant in ABCC8 has been reported in at least 10 individuals with hyperinsulinemic hypoglycemia (PMID: 12199344, 25555642, 9041101, 16429405, 32170320, 9618169, 26431509, 23275527, 10615958, 27682711, 17378627), and has been identified in 0.006% (1/15422) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs387906407). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID#: 9086) and has been interpreted as pathogenic by OMIM, Invitae, Women's Health and Genetics/Laboratory Corporation of America (LabCorp), Genetic Services Laboratory (University of Chicago), and Natera Inc. Of the 10 affected individuals, 3 were compound heterozygotes that carried a reported pathogenic variant in trans, and 2 were homozygotes, which increases the likelihood that the p.Arg1436Gln variant is pathogenic (PMID: 9041101, 26431509, 23275527). In vitro functional studies provide some evidence that the p.Arg1436Gln variant may impact protein function (PMID: 9041101, 10615958). 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, PS3_moderate, PP3, PM2_supporting (Richards 2015).
Baylor Genetics	RCV003466843	SCV004194429	pathogenic	Type 2 diabetes mellitus	2024-03-24	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000009654	SCV004806507	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2024-03-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001040039	SCV005051063	pathogenic	not provided	2024-05-01	criteria provided, single submitter	clinical testing	ABCC8: PS3, PM1, PM2, PS4:Moderate
OMIM	RCV000009654	SCV000029872	pathogenic	Hyperinsulinemic hypoglycemia, familial, 1	2020-04-30	no assertion criteria provided	literature only
Natera, Inc.	RCV001826455	SCV002077461	pathogenic	Hereditary hyperinsulinism	2020-10-09	no assertion criteria provided	clinical testing