Submissions for variant NM_000525.4(KCNJ11):c.602G>A (p.Arg201His)

dbSNP: rs80356624

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146114	SCV000193331	pathogenic	Neonatal insulin-dependent diabetes mellitus	2013-05-03	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000712160	SCV000842585	pathogenic	not provided	2020-08-25	criteria provided, single submitter	clinical testing	This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been confirmed to occur de novo in multiple individuals with clinical features associated with this gene. Additionally, there is evidence that this variant segregates with disease in multiple families. Assessment of experimental evidence suggests this variant results in abnormal protein function. Experiment showed reduced sensitivity to ATP (PMID:15718250).
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000712160	SCV001468001	pathogenic	not provided	2020-08-11	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000712160	SCV002023214	pathogenic	not provided	2019-12-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000712160	SCV002228659	pathogenic	not provided	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 201 of the KCNJ11 protein (p.Arg201His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neonatal diabetes (PMID: 15115830, 15531505, 15838686, 16670688, 24622368). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8666). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 15115830). This variant disrupts the p.Arg201 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15115830, 22768671, 26958039, 27681997). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics, Madras Diabetes Research Foundation	RCV002051777	SCV002318398	pathogenic	Neonatal diabetes mellitus		criteria provided, single submitter	clinical testing
GeneDx	RCV000712160	SCV002504203	pathogenic	not provided	2024-05-02	criteria provided, single submitter	clinical testing	Published in vitro functional studies suggest a damaging effect due to reduced ATP sensitivity leading to a loss of insulin secretion in response to metabolic stimulation (Tarasov et al., 2006); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16205880, 34566892, 16339180, 20220270, 25308342, 20466780, 20540435, 21352428, 26839896, 23434183, 23959658, 15838686, 15531505, 28460053, 16670688, 25028140, 18924582, 28480665, 19345438, 19500515, 18548275, 19247925, 32792356, 32418263, 33837025, 33240318, 30094785, 15115830, 16731837, 23462667, 16087682, 24622368, 17065345, 32893419, 33663443, 33885251, 36418577, 34671977, 37251668)
Neuberg Centre For Genomic Medicine, NCGM	RCV001089463	SCV004047817	pathogenic	Diabetes mellitus, permanent neonatal 2		criteria provided, single submitter	clinical testing	The c.602G>A (p.Arg201His) missense variant in KCNJ11 gene has been reported in individual(s) with neonatal diabetes (Gloyn et al., 2006). In at least one individual the variant was observed to be de novo. Experimental studies have shown that this missense change affects KCNJ11 function (Gloynet al., 2004). This variant disrupts the p.Arg201Cys amino acid residue in KCNJ11. The p.Arg201His variant is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. The amino acid Arg at position 201 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg201His in KCNJ11 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as likely Pathogenic.
OMIM	RCV001089463	SCV000029415	pathogenic	Diabetes mellitus, permanent neonatal 2	2006-07-01	no assertion criteria provided	literature only
OMIM	RCV000009200	SCV000029417	pathogenic	Diabetes mellitus, transient neonatal, 3	2006-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000009198	SCV000040738	not provided	Permanent neonatal diabetes mellitus		no assertion provided	literature only
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002227021	SCV002505934	uncertain significance	Hyperinsulinemia		flagged submission	research	Mutations in KCNJ11 gene can generally cause decreased production and secretion of insulin. This can lead to MODY. However, this particular variant (rs80356624) prevalence is seen in congenital hyperinsulinism and no sufficient evidence is seen to ascertain its significance in MODY yet.