NM_000085.5(CLCNKB):c.1313G>A (p.Arg438His) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Feb 1, 2024
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:: RCV002938123.9

Allele description [Variation Report for NM_000085.5(CLCNKB):c.1313G>A (p.Arg438His)]

NM_000085.5(CLCNKB):c.1313G>A (p.Arg438His)

Genes:

LOC106501713:CLCNKB recombination region [Gene]
CLCNKB:chloride voltage-gated channel Kb [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.13

Genomic location:

Preferred name:

NM_000085.5(CLCNKB):c.1313G>A (p.Arg438His)

HGVS:

NC_000001.11:g.16051725G>A
NG_013079.1:g.12974G>A
NG_013079.2:g.12945G>A
NG_042865.1:g.7233G>A
NM_000085.4:c.1313G>A
NM_000085.5:c.1313G>AMANE SELECT
NM_001165945.2:c.806G>A
NP_000076.2:p.Arg438His
NP_001159417.2:p.Arg269His
NC_000001.10:g.16378220G>A

Protein change:

R269H

Molecular consequence:

NM_000085.5:c.1313G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001165945.2:c.806G>A - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV003266105	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2023)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 9326936, 10831588, 11734858, 21631963, 31115572, 23703872, 10906158, 28381550, 32857947, 28492532
SCV004700049	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Feb 1, 2024)	germline	clinical testing	Citation Link,
SCV005325108	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 26, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003266105

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 22, 2023)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

SCV004700049

CeGaT Center for Human Genetics Tuebingen

criteria provided, single submitter

(CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)

Pathogenic
(Feb 1, 2024)

germline

clinical testing

Citation Link,

SCV005325108

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 26, 2023)

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	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in the chloride channel gene, CLCNKB, cause Bartter's syndrome type III.

Simon DB, Bindra RS, Mansfield TA, Nelson-Williams C, Mendonca E, Stone R, Schurman S, Nayir A, Alpay H, Bakkaloglu A, Rodriguez-Soriano J, Morales JM, Sanjad SA, Taylor CM, Pilz D, Brem A, Trachtman H, Griswold W, Richard GA, John E, Lifton RP.

Nat Genet. 1997 Oct;17(2):171-8.

PubMed [citation]

PMID:: 9326936

Functional and structural analysis of ClC-K chloride channels involved in renal disease.

Waldegger S, Jentsch TJ.

J Biol Chem. 2000 Aug 11;275(32):24527-33.

PubMed [citation]

PMID:: 10831588

See all PubMed Citations (10)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003266105.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg438 amino acid residue in CLCNKB. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9326936, 10831588, 11734858, 21631963, 28381550, 31115572). 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 CLCNKB function (PMID: 23703872). 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 CLCNKB protein function. This missense change has been observed in individual(s) with clinical features of CLCNKB-related conditions (PMID: 10906158, 28381550, 32857947). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs201540273, gnomAD 0.005%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 438 of the CLCNKB protein (p.Arg438His).

#	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 CeGaT Center for Human Genetics Tuebingen, SCV004700049.6

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

Description

CLCNKB: PM3:Strong, PM2, PM5, PP3, PS3:Supporting

#	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		1	not provided	not provided	not provided

From GeneDx, SCV005325108.1

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

Description

Published functional studies demonstrate p.(R438H) significantly affects voltage-gated chloride channel function (PMID: 23703872); 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: 34426522, 28555925, 12472765, 34246755, 28381550, 32857947, 10906158, 23703872)

#	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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