The relationship between SLC12A1 (Solute carrier family 12, member1, Na-K-Cl transporter 2, previously known as NKCC2) and antenatal Bartter syndrome was evaluated using the ClinGen Clinical Validity Framework. The SLC12A1 gene encodes a Na-K-Cl transporter protein that mediates Na and Cl reabsorption, accounts for most NaCl reabsorption and has a key role in concentrating urine. SLC12A1 was first reported in relation to antenatal Bartter syndrome by Simon in 1996 PMID:8640224. Antenatal Bartter syndrome is the only disease associated with pathogenic variants in this gene. Many variants have been reported in SLC12A1 including nonsense and missense variants in many publications and public databases. The maximum score for genetic evidence was reached. The mechanism of pathogenicity is Loss of Function. This gene-disease association is also supported by experimental expression, biochemical function, functional alteration in non-patient cells and in a non-human model organism. In summary, SLC12A1 is definitively associated with Antenatal Bartter syndrome. This has been demonstrated in both the clinical diagnostic and research setting, and has been upheld over time. This assessment was performed according to the ClinGen Gene Clinical Validity SOP version 8 and was approved by the Tubulopathy Working Group on 21 April 2022.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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