Submissions for variant NM_000525.4(KCNJ11):c.601C>T (p.Arg201Cys)

dbSNP: rs80356625

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000146113	SCV000193330	pathogenic	Diabetes mellitus	2013-02-08	criteria provided, single submitter	clinical testing
Beijing Key Laboratry for Genetics of Birth Defects, Beijing Children's Hospital	RCV001530196	SCV001739488	pathogenic	Diabetes mellitus, transient neonatal, 3	2020-02-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851755	SCV002247434	pathogenic	not provided	2023-12-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 201 of the KCNJ11 protein (p.Arg201Cys). 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, 22768671, 26958039, 27681997). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 8668). 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%. Studies have shown that this missense change alters KCNJ11 gene expression (PMID: 16731837). This variant disrupts the p.Arg201 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been observed in individuals with KCNJ11-related conditions (PMID: 15115830, 27681997), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Molecular Genetics, Madras Diabetes Research Foundation	RCV002051779	SCV002318396	pathogenic	Neonatal diabetes mellitus		criteria provided, single submitter	clinical testing
OMIM	RCV001089465	SCV000029420	pathogenic	Diabetes mellitus, permanent neonatal 2	2005-01-01	no assertion criteria provided	literature only
GeneReviews	RCV000009202	SCV000040737	not provided	Permanent neonatal diabetes mellitus		no assertion provided	literature only
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002227023	SCV002506482	uncertain significance	Maturity onset diabetes mellitus in young		flagged submission	research	Mutations in KCNJ11 gene can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. Though the prevalence of this particular variant rs80356625 is seen in neonatal diabetes and hyperinsulinism, no sufficient evidence found for its significance in MODY yet.
Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic	RCV002227024	SCV002506484	benign	Transitory neonatal diabetes mellitus		flagged submission	research	Mutations in KCNJ11 can cause decreased production and secretion of insulin. This can lead to MODY which may be responsive to oral sulfonylureas. The prevalence of this particular variant rs80356625 is seen in neonatal diabetes and hyperinsulinism. However, since the variant is too frequent in different ethnic groups to cause the disease, it is categorized as a benign variant.