NM_000525.4(KCNJ11):c.406C>T (p.Arg136Cys) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 21, 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:: RCV002524208.5

Allele description [Variation Report for NM_000525.4(KCNJ11):c.406C>T (p.Arg136Cys)]

NM_000525.4(KCNJ11):c.406C>T (p.Arg136Cys)

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.406C>T (p.Arg136Cys)

HGVS:

NC_000011.10:g.17387686G>A
NG_012446.1:g.5974C>T
NM_000525.4:c.406C>TMANE SELECT
NM_001166290.2:c.145C>T
NM_001377296.1:c.145C>T
NM_001377297.1:c.145C>T
NP_000516.3:p.Arg136Cys
NP_000516.3:p.Arg136Cys
NP_001159762.1:p.Arg49Cys
NP_001364225.1:p.Arg49Cys
NP_001364226.1:p.Arg49Cys
NC_000011.9:g.17409233G>A
NM_000525.3:c.406C>T

Protein change:

R136C

Links:

dbSNP: rs766891274

NCBI 1000 Genomes Browser:

rs766891274

Molecular consequence:

NM_000525.4:c.406C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001166290.2:c.145C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377296.1:c.145C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001377297.1:c.145C>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
SCV003439791	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 21, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 21422196, 20686794, 28442472, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003439791

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 21, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

Characterization of ABCC8 and KCNJ11 gene mutations and phenotypes in Korean patients with congenital hyperinsulinism.

Park SE, Flanagan SE, Hussain K, Ellard S, Shin CH, Yang SW.

Eur J Endocrinol. 2011 Jun;164(6):919-26. doi: 10.1530/EJE-11-0160. Epub 2011 Mar 21. Erratum in: Eur J Endocrinol. 2011 Sep;165(3):485-6.

PubMed [citation]

PMID:: 21422196

An Egyptian case of congenital hyperinsulinism of infancy due to a novel mutation in KCNJ11 encoding Kir6.2 and response to octreotide.

Sherif EM, Abdelmaksoud AA, Elbarbary NS, Njølstad PR.

Acta Diabetol. 2013 Oct;50(5):801-5. doi: 10.1007/s00592-010-0217-1. Epub 2010 Aug 5.

PubMed [citation]

PMID:: 20686794

See all PubMed Citations (4)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003439791.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 136 of the KCNJ11 protein (p.Arg136Cys). This variant is present in population databases (rs766891274, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive congenital hyperinsulinism (PMID: 21422196). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 435558). 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%. This variant disrupts the p.Arg136 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 20686794, 28442472). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

#	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

Last Updated: Sep 29, 2024

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