ClinVar Miner

Submissions for variant NM_000525.4(KCNJ11):c.100C>T (p.Arg34Cys)

gnomAD frequency: 0.00001  dbSNP: rs954727530
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000673558 SCV000798774 likely pathogenic Permanent neonatal diabetes mellitus; Diabetes mellitus, transient neonatal, 3; Hyperinsulinemic hypoglycemia, familial, 2 2018-03-24 criteria provided, single submitter clinical testing
Invitae RCV001855597 SCV002265480 pathogenic not provided 2023-07-25 criteria provided, single submitter clinical testing 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 KCNJ11 protein function. ClinVar contains an entry for this variant (Variation ID: 557416). This missense change has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 23275527, 27908292). This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 34 of the KCNJ11 protein (p.Arg34Cys). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg34 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15807877, 24421282, 24686051). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 12524280, 23275527).
Molecular Genetics, Royal Melbourne Hospital RCV002225111 SCV002503870 likely pathogenic Monogenic diabetes 2023-03-30 criteria provided, single submitter clinical testing This sequence change is predicted to replace arginine with cysteine at codon 34 of the KCNJ11 protein, p.(Arg34Cys). The arginine residue is highly conserved (100 vertebrates, UCSC), and is located in the cytoplasmic N-terminus domain. There is a large physicochemical difference between arginine and cysteine. The variant is present in a large population cohort at an allele frequency of 0.0004% (rs954727530, 1/250,946 alleles in gnomAD v2.1). KCNJ11 has a low tolerance for missense variation and missense change is the predominant mutational mechanism (gnomAD v2.1, DECIPHER, ClinVar). Three probands have been described with this variant with transient neonatal diabetes and congenital hyperinsulinism (PMID: 27908292; 23275527; 17446535). Expression studies show a defect in trafficking (PMID: 12524280). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). An alternate change at the same amino acid residue determine to be pathogenic, p.(Arg34His), has been reported in individuals with congenital hyperinsulinism in monoallelic and biallelic forms (PMID: 31218401, 28270372, 24421282, 24686051, 20685672). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PM2, PM5, PS3_Supporting, PS4_Supporting, PP2, PP3.
Baylor Genetics RCV003459641 SCV004198070 likely pathogenic Type 2 diabetes mellitus 2023-02-25 criteria provided, single submitter clinical testing
Athena Diagnostics RCV001855597 SCV004229760 likely pathogenic not provided 2023-04-07 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 individuals with transient neonatal diabetes and others with focal congenital hyperinsulinism. Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 12524280)

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