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:: RCV001817986.10

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002069645	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely pathogenic (Nov 17, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002296176	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Mar 8, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 31464105, 12524280, 25555642, 27908292, 30026763, 28492532
SCV002588047	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Oct 24, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002069645

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely pathogenic
(Nov 17, 2020)

germline

clinical testing

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

SCV002296176

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Mar 8, 2023)

germline

clinical testing

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

SCV002588047

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Oct 24, 2022)

germline

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002296176.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical 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).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV002588047.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not 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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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