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NM_000525.4(KCNJ11):c.601C>T (p.Arg201Cys) AND Diabetes mellitus, permanent neonatal 2

Germline classification:
Pathogenic (2 submissions)
Last evaluated:
Sep 29, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV001089465.10

Allele description [Variation Report for NM_000525.4(KCNJ11):c.601C>T (p.Arg201Cys)]

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

Gene:
KCNJ11:potassium inwardly rectifying channel subfamily J member 11 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
11p15.1
Genomic location:
Preferred name:
NM_000525.4(KCNJ11):c.601C>T (p.Arg201Cys)
HGVS:
  • NC_000011.10:g.17387491G>A
  • NG_012446.1:g.6169C>T
  • NM_000525.4:c.601C>TMANE SELECT
  • NM_001166290.2:c.340C>T
  • NM_001377296.1:c.340C>T
  • NM_001377297.1:c.340C>T
  • NP_000516.3:p.Arg201Cys
  • NP_000516.3:p.Arg201Cys
  • NP_001159762.1:p.Arg114Cys
  • NP_001364225.1:p.Arg114Cys
  • NP_001364226.1:p.Arg114Cys
  • NC_000011.9:g.17409038G>A
  • NM_000525.3:c.601C>T
Protein change:
R114C; ARG201CYS
Links:
OMIM: 600937.0004; dbSNP: rs80356625
NCBI 1000 Genomes Browser:
rs80356625
Molecular consequence:
  • NM_000525.4:c.601C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001166290.2:c.340C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377296.1:c.340C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377297.1:c.340C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Diabetes mellitus, permanent neonatal 2
Identifiers:
MONDO: MONDO:0030087; MedGen: C5394296; OMIM: 618856

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000029420OMIM
no assertion criteria provided
Pathogenic
(Jan 1, 2005)
germlineliterature only

PubMed (5)
[See all records that cite these PMIDs]

SCV006059852Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSLVariantClassificationCriteria RUGD 01 April 2020)
Pathogenic
(Sep 29, 2023)
unknownclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlinenot providednot providednot providednot providednot providednot providedliterature only
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Molecular basis for Kir6.2 channel inhibition by adenine nucleotides.

Ribalet B, John SA, Weiss JN.

Biophys J. 2003 Jan;84(1):266-76.

PubMed [citation]
PMID:
12524280
PMCID:
PMC1302608

Molecular basis of Kir6.2 mutations associated with neonatal diabetes or neonatal diabetes plus neurological features.

Proks P, Antcliff JF, Lippiat J, Gloyn AL, Hattersley AT, Ashcroft FM.

Proc Natl Acad Sci U S A. 2004 Dec 14;101(50):17539-44. Epub 2004 Dec 6.

PubMed [citation]
PMID:
15583126
PMCID:
PMC536014
See all PubMed Citations (9)

Details of each submission

From OMIM, SCV000029420.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedliterature only PubMed (5)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot providednot providednot providednot providednot provided

From Illumina Laboratory Services, Illumina, SCV006059852.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

The KCNJ11 c.601C>T p.(Arg201Cys) missense variant has been identified in individuals with permanent neonatal diabetes mellitus (PNDM), including in a de novo state in at least two individuals (PMID: 15115830; 25555642; 26958039; 32027066; 34566892). Additionally, a different amino acid substitution at the same position (p.Arg201His) has been reported in individuals with similar phenotype (PMID: 32027066). The c.601C>T variant is not observed in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. Multiple lines of computational evidence suggest the variant may impact the gene or gene product. This variant was identified in a de novo state in the proband. Based on the available evidence, the c.601C>T p.(Arg201Cys) variant is classified as pathogenic for monogenic diabetes.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jun 22, 2025