NM_000085.5(CLCNKB):c.610G>A (p.Ala204Thr) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Jan 26, 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:: RCV001280721.9

Allele description [Variation Report for NM_000085.5(CLCNKB):c.610G>A (p.Ala204Thr)]

NM_000085.5(CLCNKB):c.610G>A (p.Ala204Thr)

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.610G>A (p.Ala204Thr)

HGVS:

NC_000001.11:g.16048537G>A
NG_013079.1:g.9786G>A
NG_042865.1:g.4045G>A
NM_000085.5:c.610G>AMANE SELECT
NP_000076.2:p.Ala204Thr
NP_000076.2:p.Ala204Thr
NC_000001.10:g.16375032G>A
NM_000085.4:c.610G>A
P51801:p.Ala204Thr

Protein change:

A204T; ALA204THR

Links:

UniProtKB: P51801#VAR_001625; OMIM: 602023.0002; dbSNP: rs121909132

NCBI 1000 Genomes Browser:

rs121909132

Molecular consequence:

NM_000085.5:c.610G>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
SCV001468035	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 19, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001816869	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 8, 2021)	germline	clinical testing	Citation Link,
SCV003523168	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 26, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 9326936, 24830959, 15875219, 31803959, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001468035

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 19, 2020)

germline

clinical testing

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

SCV001816869

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Oct 8, 2021)

germline

clinical testing

Citation Link,

SCV003523168

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 26, 2024)

germline

clinical testing

PubMed (5)
[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

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

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

See all PubMed Citations (6)

Details of each submission

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV001468035.1

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

Description

PS3, PP3, PM1, PM2, PM3

#	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 GeneDx, SCV001816869.3

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

Description

Reported as a founder mutation in individuals of Spanish ancestry, with variable phenotypic presentation (Garca Castao et al., 2017); Published functional studies suggest a damaging effect due to altered gating properties resulting from decreased sensitivity to extracellular pH and Ca2+ (Bignon et al., 2020); 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: 20931281, 9326936, 31803959, 16391491, 24830959, 28288174, 24058621, 31589614, 33532864, 28381550, 15875219, 31672324)

#	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, SCV003523168.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 204 of the CLCNKB protein (p.Ala204Thr). This variant is present in population databases (rs121909132, gnomAD 0.04%). This missense change has been observed in individual(s) with Bartter syndrome and Gitelman syndrome (PMID: 9326936, 15875219, 24830959). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of Spanish ancestry (PMID: 15875219). ClinVar contains an entry for this variant (Variation ID: 7592). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CLCNKB protein function. Experimental studies have shown that this missense change affects CLCNKB function (PMID: 31803959). 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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