ClinVar Miner

Submissions for variant NM_000352.6(ABCC8):c.4198G>A (p.Gly1400Arg)

gnomAD frequency: 0.00004  dbSNP: rs137852676
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000029263 SCV000051909 likely pathogenic Familial hyperinsulinism 2022-05-06 criteria provided, single submitter clinical testing Variant summary: ABCC8 c.4198G>A (p.Gly1400Arg) 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 195184 control chromosomes. c.4198G>A has been reported in the literature as a heterozygous and compound heterozygous genotype in individuals affected with focal and diffuse forms of Congenital Hyperinsulinism (example, Stanley_2004, Suchi_2006, Greer_2007, Ellard_2007, Rafiq_2008, Sandal_2009, Dastamani_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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 pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl RCV000169150 SCV000220375 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2014-06-07 criteria provided, single submitter literature only
Invitae RCV001390783 SCV001592625 pathogenic not provided 2021-12-03 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1400 of the ABCC8 protein (p.Gly1400Arg). This variant also falls at the last nucleotide of exon 34, which is part of the consensus splice site for this exon. This variant is present in population databases (rs137852676, gnomAD 0.001%). This missense change has been observed in individual(s) with autosomal recessive neonatal diabetes and congenital hyperinsulinism (PMID: 17668386, 19475716). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as Gly1401Arg. ClinVar contains an entry for this variant (Variation ID: 35616). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects ABCC8 function (PMID: 22802590, 31464105). 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.
Myriad Women's Health, Inc. RCV000169150 SCV002060366 likely pathogenic Hyperinsulinemic hypoglycemia, familial, 1 2021-10-20 criteria provided, single submitter clinical testing NM_000352.3(ABCC8):c.4198G>A(G1400R) is a missense variant classified as likely pathogenic in the context of ABCC8-related hyperinsulinism. G1400R has been observed in cases with relevant disease (PMID: 31464105, 23275527, 17378627, 19475716, 17919176, 30114684). Functional assessments of this variant are available in the literature (PMID: 22802590, 31464105). G1400R has been observed in population frequency databases (gnomAD: NFE 0%). In summary, NM_000352.3(ABCC8):c.4198G>A(G1400R) is a missense variant that has been observed more frequently in cases with the relevant disease than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Genetic Services Laboratory,University of Chicago RCV001390783 SCV002069224 pathogenic not provided 2018-07-27 criteria provided, single submitter clinical testing
OMIM RCV000009657 SCV000029875 pathogenic Diabetes mellitus, permanent neonatal 3 2007-08-01 no assertion criteria provided literature only
Natera, Inc. RCV001277179 SCV001464077 likely pathogenic Hereditary hyperinsulinism 2020-09-16 no assertion criteria provided clinical testing

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