ClinVar Miner

Submissions for variant NM_000085.5(CLCNKB):c.226C>T (p.Arg76Ter)

gnomAD frequency: 0.00001  dbSNP: rs370985865
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001251481 SCV001427134 pathogenic Epilepsy, familial focal, with variable foci 1 2018-11-27 criteria provided, single submitter clinical testing A homozygous nonsense variant, NM_000085.4(CLCNKB):c.226C>T, has been identified in exon 3 of 20 of the CLCNKB gene (NB: This variant is non-coding in alternative transcripts). The variant is predicted to result in a premature stop codon at position 76 of the protein (NP_000076.2(CLCNKB):p.(Arg76*)). This variant is predicted to result in loss of protein function through nonsense-mediated decay (NMD), which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.001% (3 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic in a patient with salt-losing tubulopathies (Nozu, K. et al., 2010). Several truncating variants predicted to result in NMD have been reported pathogenic (ClinVar, HGMD, Decipher). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
GeneDx RCV002254959 SCV002526168 pathogenic not provided 2021-12-08 criteria provided, single submitter clinical testing Reported in individuals with Bartter syndrome or Gitelman syndrome who harbored a second pathogenic CLCNKB variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in all cases (Nozu et al., 2010; Hureaux et al., 2019); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 32939031, 31672324, 28381550, 30773290, 20810575)
Fulgent Genetics, Fulgent Genetics RCV002480867 SCV002780816 pathogenic Bartter disease type 3; Bartter disease type 4B 2023-12-26 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV002254959 SCV004291598 pathogenic not provided 2023-08-10 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 975076). This premature translational stop signal has been observed in individual(s) with CLCNKB-related conditions (PMID: 20810575, 28381550, 30773290). This variant is present in population databases (rs370985865, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Arg76*) in the CLCNKB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CLCNKB are known to be pathogenic (PMID: 24830959, 26920127, 28381550, 29254190).
Yale Center for Mendelian Genomics, Yale University RCV001849489 SCV002106615 pathogenic Bartter disease type 3 2019-02-14 no assertion criteria provided literature only

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