NM_000085.5(CLCNKB):c.1325A>G (p.Glu442Gly) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Aug 11, 2021
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:: RCV000991835.6

Allele description [Variation Report for NM_000085.5(CLCNKB):c.1325A>G (p.Glu442Gly)]

NM_000085.5(CLCNKB):c.1325A>G (p.Glu442Gly)

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.1325A>G (p.Glu442Gly)

HGVS:

NC_000001.11:g.16051737A>G
NG_013079.1:g.12986A>G
NG_042865.1:g.7245A>G
NM_000085.5:c.1325A>GMANE SELECT
NM_001165945.2:c.818A>G
NP_000076.2:p.Glu442Gly
NP_001159417.2:p.Glu273Gly
NC_000001.10:g.16378232A>G
NC_000001.10:g.16378232A>G
NM_000085.3:c.1325A>G

Protein change:

E273G

Links:

dbSNP: rs1180658535

NCBI 1000 Genomes Browser:

rs1180658535

Molecular consequence:

NM_000085.5:c.1325A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001165945.2:c.818A>G - 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
SCV001143609	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Oct 16, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 28555925, 24058621, 24830959, 25810436, 28288174, 26467025
SCV002246402	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 11, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 24058621, 28555925, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001143609

Athena Diagnostics

criteria provided, single submitter

(Athena Diagnostics Criteria)

Likely pathogenic
(Oct 16, 2018)

germline

clinical testing

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

SCV002246402

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 11, 2021)

germline

clinical testing

PubMed (3)
[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

A labor- and cost-effective non-optical semiconductor (Ion Torrent) next-generation sequencing of the SLC12A3 and CLCNKA/B genes in Gitelman's syndrome patients.

Tavira B, Gómez J, Santos F, Gil H, Alvarez V, Coto E.

J Hum Genet. 2014 Jul;59(7):376-80. doi: 10.1038/jhg.2014.37. Epub 2014 May 15.

PubMed [citation]

PMID:: 24830959

ClC-K chloride channels: emerging pathophysiology of Bartter syndrome type 3.

Andrini O, Keck M, Briones R, Lourdel S, Vargas-Poussou R, Teulon J.

Am J Physiol Renal Physiol. 2015 Jun 15;308(12):F1324-34. doi: 10.1152/ajprenal.00004.2015. Epub 2015 Mar 25. Review.

PubMed [citation]

PMID:: 25810436

See all PubMed Citations (7)

Details of each submission

From Athena Diagnostics, SCV001143609.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The best available variant frequency is uninformative because there are too few occurrences in population data. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Inconclusive functional study. Occurs in three or more cases with a recessive pathogenic variant in the same gene.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002246402.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces glutamic acid with glycine at codon 442 of the CLCNKB protein (p.Glu442Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individuals with Bartter syndrome (PMID: 24058621). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 804713). 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. Studies have shown that this missense change alters CLCNKB gene expression (PMID: 28555925). 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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