VCV000008668.16 - ClinVar

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

Interpretation:: Conflicting interpretations of pathogenicity
Pathogenic(4); Uncertain significance(1); Benign(1)
Review status:: criteria provided, conflicting interpretations
Submissions:: 8
First in ClinVar:: Apr 4, 2013
Most recent Submission:: Feb 7, 2023
Last evaluated:: Jul 12, 2021
Accession:: VCV000008668.16
Variation ID:: 8668
Description:: single nucleotide variant

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

Allele ID

23707

Variant type

single nucleotide variant

Variant length

1 bp

Cytogenetic location

11p15.1

Genomic location

11: 17387491 (GRCh38) GRCh38 UCSC

11: 17409038 (GRCh37) GRCh37 UCSC

HGVS

Nucleotide	Protein	Molecular consequence
NM_000525.4:c.601C>T MANE Select	NP_000516.3:p.Arg201Cys	missense
NM_001166290.2:c.340C>T	NP_001159762.1:p.Arg114Cys	missense
NM_001377296.1:c.340C>T	NP_001364225.1:p.Arg114Cys	missense
NM_001377297.1:c.340C>T	NP_001364226.1:p.Arg114Cys	missense
NC_000011.10:g.17387491G>A
NC_000011.9:g.17409038G>A
NG_012446.1:g.6169C>T

... more HGVS ... less HGVS

Protein change

R201C, R114C

Other names

Canonical SPDI

NC_000011.10:17387490:G:A

Functional consequence

Global minor allele frequency (GMAF)

Allele frequency

Links

ClinGen: CA119825

OMIM: 600937.0004

dbSNP: rs80356625

VarSome

Aggregate interpretations per condition

Interpreted condition	Interpretation	Number of submissions	Review status	Last evaluated	Variation/condition record
Diabetes mellitus	Pathogenic	1	criteria provided, single submitter	Feb 8, 2013	RCV000146113.5
Diabetes mellitus, transient neonatal, 3	Pathogenic	1	criteria provided, single submitter	Feb 28, 2020	RCV001530196.2
not provided	Pathogenic	1	criteria provided, single submitter	Jul 12, 2021	RCV001851755.5
Transitory neonatal diabetes mellitus	Benign	1	criteria provided, single submitter	-	RCV002227024.2
Neonatal diabetes mellitus	Pathogenic	1	criteria provided, single submitter	-	RCV002051779.2
Maturity onset diabetes mellitus in young	Uncertain significance	1	criteria provided, single submitter	-	RCV002227023.2
Diabetes mellitus, permanent neonatal 2	Pathogenic	1	no assertion criteria provided	Jan 1, 2005	RCV001089465.3
Permanent neonatal diabetes mellitus	not provided	1	no assertion provided	-	RCV000009202.9

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation viewer	Related variants
Gene	OMIM	HI score Help	TS score Help	Variation viewer	Within gene	All
KCNJ11		-	-	GRCh38 GRCh37	394	419

Submitted interpretations and evidence

Interpretation (Last evaluated)	Review status (Assertion criteria)	Condition (Inheritance)	Submitter	More information
Pathogenic (Feb 08, 2013)	criteria provided, single submitter (ACMG Guidelines, 2007) Method: clinical testing	Diabetes mellitus (Autosomal unknown) Affected status: yes Allele origin: germline	Genetic Services Laboratory,University of Chicago Accession: SCV000193330.1 First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014
Uncertain significance (-)	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research	Maturity onset diabetes mellitus in young (Autosomal dominant inheritance) Affected status: unknown Allele origin: somatic	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV002506482.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Publications: PubMed (2) PubMed: 34566892‚ 25555642 Comment: 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 … (more) 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. (less)
Benign (-)	criteria provided, single submitter (K & H Uppaluri Personalized Medicine Clinic Variant Classification & Assertion Criteria_Updated V.1) Method: research	Transitory neonatal diabetes mellitus (Autosomal dominant inheritance) Affected status: yes Allele origin: somatic	Clinical Genomics, Uppaluri K&H Personalized Medicine Clinic Accession: SCV002506484.1 First in ClinVar: May 07, 2022 Last updated: May 07, 2022	Publications: PubMed (2) PubMed: 34566892‚ 25555642 Comment: 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 … (more) 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. (less)
Pathogenic (Feb 28, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Diabetes mellitus, transient neonatal, 3 Affected status: yes Allele origin: de novo	Beijing Key Laboratry for Genetics of Birth Defects,Beijing Children's Hospital Accession: SCV001739488.1 First in ClinVar: Jul 07, 2021 Last updated: Jul 07, 2021	Number of individuals with the variant: 1 Age: 0-9 years Sex: male Ethnicity/Population group: East asia Geographic origin: China Testing laboratory: Liwei's Lab
Pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Neonatal diabetes mellitus Affected status: yes Allele origin: germline	Molecular Genetics,Madras Diabetes Research Foundation Accession: SCV002318396.1 First in ClinVar: Apr 02, 2022 Last updated: Apr 02, 2022	Publications: PubMed (1) PubMed: 32893419 Ethnicity/Population group: Indians Geographic origin: India
Pathogenic (Jul 12, 2021)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Invitae Accession: SCV002247434.2 First in ClinVar: Mar 28, 2022 Last updated: Feb 07, 2023	Publications: PubMed (5) PubMed: 15115830‚ 22768671‚ 26958039‚ 27681997‚ 16731837 Comment: This sequence change replaces arginine with cysteine at codon 201 of the KCNJ11 protein (p.Arg201Cys). The arginine residue is highly conserved and there is a … (more) This sequence change replaces arginine with cysteine at codon 201 of the KCNJ11 protein (p.Arg201Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC 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. 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. (less)
Pathogenic (Jan 01, 2005)	no assertion criteria provided Method: literature only	DIABETES MELLITUS, PERMANENT NEONATAL, 2 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000029420.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 07, 2020	Publications: PubMed (4) PubMed: 12524280‚ 15583126‚ 15580558‚ 15292329 Gloyn, A. L., Pearson, E. R., (more...) Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004. Comment on evidence: In a patient with permanent neonatal diabetes mellitus (PNDM2; 618856), Gloyn et al. (2004) identified a heterozygous arg201-to-cys (R201C) mutation in the Kir6.2 gene. The … (more) In a patient with permanent neonatal diabetes mellitus (PNDM2; 618856), Gloyn et al. (2004) identified a heterozygous arg201-to-cys (R201C) mutation in the Kir6.2 gene. The patient was diagnosed at 4 weeks of age and had no additional neurologic or dysmorphic features. The arg201 residue lies close to the ATP-binding site and was implicated in ATP sensitivity (Ribalet et al., 2003). Proks et al. (2004) stated that the 2 mutations in residue arg201, R201H (600937.0002) and R201C, which lie in the ATP-binding site of Kir6.2, cause milder PNDM disease without neurologic features; however, Massa et al. (2005) identified the R201C mutation in a patient with PNDM who also had muscle weakness and delayed motor development. Gloyn et al. (2004) described a family in which 2 affected paternal half-sibs were heterozygous for the R201C mutation. Direct sequencing of leukocyte DNA showed that their clinically unaffected mothers and father were genotypically normal. Quantitative real-time PCR analysis of the father's leukocyte DNA detected no trace of mutant DNA. These results were consistent with the father being mosaic for the mutation, which was restricted to his germline. Gloyn et al. (2004) concluded that the high percentage of permanent neonatal diabetes cases due to de novo KCNJ11 mutations (Gloyn et al., 2004) suggests that germline mosaicism may be common. (less)
not provided (-)	no assertion provided Method: literature only	Permanent neonatal diabetes mellitus Affected status: not provided Allele origin: unknown	GeneReviews Accession: SCV000040737.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 01, 2022	Publications: PubMed (6) PubMed: 12524280‚ 15115830‚ 15580558‚ 15583126‚ 16123337‚ 20301620 BookShelf: NBK1447 BookShelf: NBK1447

Citation text

Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.

Comment:

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.

Comment:

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.

Comment:

This sequence change replaces arginine with cysteine at codon 201 of the KCNJ11 protein (p.Arg201Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC 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. 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.

Functional evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for this variant

Title	Author	Journal	Year	Link
Molecular Genetics, Clinical Characteristics, and Treatment Outcomes of K(ATP)-Channel Neonatal Diabetes Mellitus in Vietnam National Children's Hospital.	Ngoc CTB	Frontiers in endocrinology	2021	PMID: 34566892
Genotype-phenotype correlation of K(ATP) channel gene defects causing permanent neonatal diabetes in Indian patients.	Gopi S	Pediatric diabetes	2021	PMID: 32893419
Molecular and clinical features of K(ATP) -channel neonatal diabetes mellitus in Japan.	Hashimoto Y	Pediatric diabetes	2017	PMID: 27681997
Permanent Neonatal Diabetes Mellitus.	Adam MP	-	2016	PMID: 20301620
Permanent Neonatal Diabetes Mellitus.	Adam MP	-	2016	BookShelf: NBK1447
Permanent neonatal diabetes mellitus - a case report of a rare cause of diabetes mellitus in East Africa.	Nyangabyaki-Twesigye C	African health sciences	2015	PMID: 26958039
Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism.	Bennett JT	Molecular genetics and metabolism	2015	PMID: 25555642
Permanent neonatal diabetes mellitus due to KCNJ11 mutation in a Portuguese family: transition from insulin to oral sulfonylureas.	Dupont J	Journal of pediatric endocrinology & metabolism : JPEM	2012	PMID: 22768671
Kir6.2 mutations associated with neonatal diabetes reduce expression of ATP-sensitive K+ channels: implications in disease mechanism and sulfonylurea therapy.	Lin CW	Diabetes	2006	PMID: 16731837
Activating mutations in Kir6.2 and neonatal diabetes: new clinical syndromes, new scientific insights, and new therapy.	Hattersley AT	Diabetes	2005	PMID: 16123337
KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes.	Massa O	Human mutation	2005	PMID: 15580558
Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.	Proks P	Proceedings of the National Academy of Sciences of the United States of America	2004	PMID: 15583126
Permanent neonatal diabetes due to paternal germline mosaicism for an activating mutation of the KCNJ11 Gene encoding the Kir6.2 subunit of the beta-cell potassium adenosine triphosphate channel.	Gloyn AL	The Journal of clinical endocrinology and metabolism	2004	PMID: 15292329
Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes.	Gloyn AL	The New England journal of medicine	2004	PMID: 15115830
Molecular basis for Kir6.2 channel inhibition by adenine nucleotides.	Ribalet B	Biophysical journal	2003	PMID: 12524280
Gloyn, A. L., Pearson, E. R., Antcliff, J. F., Proks, P., Bruining, G. J., Slingerland, A. S., Howard, N., Srinivasan, S., Silva, J. M. C. L., Molnes, J., Edghill, E. L., Frayling, T. M., and 13 others Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. New Eng. J. Med. 350: 1838-1849, 2004. Note: Erratum: New Eng. J. Med. 351: 1470 only, 2004.	-	-	-	-

Text-mined citations for rs80356625...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Feb 07, 2023

ClinVar Genomic variation as it relates to human health

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

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

Aggregate interpretations per condition

Submitted interpretations and evidence

Functional evidence

Citations for this variant

Text-mined citations for rs80356625...