U.S. flag

An official website of the United States government

NM_000525.4(KCNJ11):c.616C>T (p.Arg206Cys) AND not provided

Germline classification:
Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:
Mar 8, 2023
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
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:
RCV001817986.9

Allele description [Variation Report for NM_000525.4(KCNJ11):c.616C>T (p.Arg206Cys)]

NM_000525.4(KCNJ11):c.616C>T (p.Arg206Cys)

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.616C>T (p.Arg206Cys)
HGVS:
  • NC_000011.10:g.17387476G>A
  • NG_012446.1:g.6184C>T
  • NM_000525.4:c.616C>TMANE SELECT
  • NM_001166290.2:c.355C>T
  • NM_001377296.1:c.355C>T
  • NM_001377297.1:c.355C>T
  • NP_000516.3:p.Arg206Cys
  • NP_001159762.1:p.Arg119Cys
  • NP_001364225.1:p.Arg119Cys
  • NP_001364226.1:p.Arg119Cys
  • NC_000011.9:g.17409023G>A
  • NM_000525.3:c.616C>T
Protein change:
R119C
Links:
dbSNP: rs775204908
NCBI 1000 Genomes Browser:
rs775204908
Molecular consequence:
  • NM_000525.4:c.616C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001166290.2:c.355C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377296.1:c.355C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001377297.1:c.355C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV002069645Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)
Likely pathogenic
(Nov 17, 2020)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002296176Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Mar 8, 2023)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV002588047GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Likely pathogenic
(Oct 24, 2022)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Novel dominant K(ATP) channel mutations in infants with congenital hyperinsulinism: Validation by in vitro expression studies and in vivo carrier phenotyping.

Boodhansingh KE, Kandasamy B, Mitteer L, Givler S, De Leon DD, Shyng SL, Ganguly A, Stanley CA.

Am J Med Genet A. 2019 Nov;179(11):2214-2227. doi: 10.1002/ajmg.a.61335. Epub 2019 Aug 28.

PubMed [citation]
PMID:
31464105
PMCID:
PMC6852436
See all PubMed Citations (7)

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV002069645.1

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

Description

The p.Arg206Cys change affects a highly conserved amino acid residue located in a domain of the KCNJ11 protein that is known to be functional. The p.Arg206Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This particular amino acid change has been described in a patient with neonatal hypoglycemia who was later diagnosed with diazoxide responsive congenital hyperinsulinism (PMID: 30026763). This variant was reported to be maternally inherited from a mother with uncontrolled gestational diabetes. It has also been reported in a family with congenital hyperinsulinism (CHI), other details not known (PMID: 25555642). Additionally, different sequence changes affecting the same amino acid residue (p.Arg206Leu and p.Arg206His) have also been described in patients with diazoxide responsive-CHI (PMIDs:31464105, 27908292). This sequence change has been described in the gnomAD database with a low population frequency of 0.0012% (dbSNP rs775204908).

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

From Invitae, SCV002296176.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg206 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 31464105; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects KCNJ11 function (PMID: 12524280). 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. ClinVar contains an entry for this variant (Variation ID: 1338615). This missense change has been observed in individuals with autosomal dominant familial hyperinsulinism (PMID: 25555642, 27908292, 30026763). This variant is present in population databases (rs775204908, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 206 of the KCNJ11 protein (p.Arg206Cys).

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

From GeneDx, SCV002588047.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

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: 12524280, 25555642, 29417725, 27908292, 30026763)

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

Last Updated: May 12, 2024