Submissions for variant NM_000525.4(KCNJ11):c.679G>A (p.Glu227Lys)

dbSNP: rs587783672

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146115	SCV000193332	pathogenic	Diabetes mellitus	2013-07-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001288659	SCV001475935	pathogenic	not provided	2024-04-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (Genome Aggregation Database (gnomAD), Cambridge, MA (URL: http://gnomad.broadinstitute.org)). This variant has been seen in multiple individuals with autosomal dominant neonatal diabetes (PMID: 4622368, 32893419, 32101525, 35114785, 35612844). It has been observed to segregate with disease within multiple unrelated families (PMID: 17327377, 17490422, 22471336) and identified as de novo in several individuals (PMID: 17327377, 33538814, 37664823). Additionally, it has been observed in individuals with later onset diabetes without confirmed history of neonatal diabetes (PMID: 32101525, 22701567, 33538814). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 17021801)
Baylor Genetics	RCV001329964	SCV001521537	pathogenic	Diabetes mellitus, transient neonatal, 3	2020-01-17	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001288659	SCV001582809	pathogenic	not provided	2024-02-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 227 of the KCNJ11 protein (p.Glu227Lys). This variant is present in population databases (rs587783672, gnomAD 0.003%). This missense change has been observed in individuals with autosomal dominant KCNJ11-related early onset diabetes (PMID: 2270156, 2462236). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 158682). 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: 17021801). For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics, Madras Diabetes Research Foundation	RCV002051813	SCV002318399	likely pathogenic	Neonatal diabetes mellitus		criteria provided, single submitter	clinical testing
OMIM	RCV000170299	SCV000222635	pathogenic	Maturity-onset diabetes of the young type 13	2012-01-01	no assertion criteria provided	literature only
Constantin Polychronakos Laboratory, The Research Institute of the McGill University Health Centre	RCV000146115	SCV001250648	pathogenic	Diabetes mellitus		no assertion criteria provided	research	PS1 PM1 PM2 PP2 PP3
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002227076	SCV002505484	benign	Maturity onset diabetes mellitus in young		flagged submission	research	Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. rs587783672(p.Glu227Lys) can lead to MODY which may be responsive to oral sulfonylureas.