NM_000525.4(KCNJ11):c.101G>A (p.Arg34His) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jun 20, 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:: RCV001588331.9

Allele description [Variation Report for NM_000525.4(KCNJ11):c.101G>A (p.Arg34His)]

NM_000525.4(KCNJ11):c.101G>A (p.Arg34His)

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.101G>A (p.Arg34His)

HGVS:

NC_000011.10:g.17387991C>T
NG_012446.1:g.5669G>A
NM_000525.4:c.101G>AMANE SELECT
NM_001166290.2:c.-16-145G>A
NM_001377296.1:c.-17+27G>A
NM_001377297.1:c.-16-145G>A
NP_000516.3:p.Arg34His
NC_000011.9:g.17409538C>T
NM_000525.3:c.101G>A

Protein change:

R34H

Links:

dbSNP: rs141145502

NCBI 1000 Genomes Browser:

rs141145502

Molecular consequence:

NM_001166290.2:c.-16-145G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001377296.1:c.-17+27G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001377297.1:c.-16-145G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000525.4:c.101G>A - 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
SCV001822658	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Sep 24, 2019)	germline	clinical testing	Citation Link,
SCV002233260	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 20, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 23275527, 27908292, 15807877, 24421282, 24686051, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001822658

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Sep 24, 2019)

germline

clinical testing

Citation Link,

SCV002233260

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jun 20, 2023)

germline

clinical testing

PubMed (6)
[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	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

Genotype and phenotype correlations in 417 children with congenital hyperinsulinism.

Snider KE, Becker S, Boyajian L, Shyng SL, MacMullen C, Hughes N, Ganapathy K, Bhatti T, Stanley CA, Ganguly A.

J Clin Endocrinol Metab. 2013 Feb;98(2):E355-63. doi: 10.1210/jc.2012-2169. Epub 2012 Dec 28.

PubMed [citation]

PMID:: 23275527
PMCID:: PMC3565119

Conservatively treated Congenital Hyperinsulinism (CHI) due to K-ATP channel gene mutations: reducing severity over time.

Salomon-Estebanez M, Flanagan SE, Ellard S, Rigby L, Bowden L, Mohamed Z, Nicholson J, Skae M, Hall C, Craigie R, Padidela R, Murphy N, Randell T, Cosgrove KE, Dunne MJ, Banerjee I.

Orphanet J Rare Dis. 2016 Dec 1;11(1):163.

PubMed [citation]

PMID:: 27908292
PMCID:: PMC5133749

See all PubMed Citations (6)

Details of each submission

From GeneDx, SCV001822658.1

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

Description

Not observed at a significant frequency or in the homozygous state in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 33144682, 32552793, 15807877, 24686051, 24421282, 31218401)

#	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, SCV002233260.3

#	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.Arg34 amino acid residue in KCNJ11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 23275527, 27908292). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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: 1219242). This missense change has been observed in individuals with autosomal recessive familial hyperinsulinism (PMID: 15807877, 24421282, 24686051). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs141145502, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 34 of the KCNJ11 protein (p.Arg34His).

#	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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