SLC26A1

Inheritance Pattern: AR

Disease ID:MONDO:0020722

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0020722

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0020722

Submitter: ClinGen

The *SLC26A1* gene is located on chromosome 4 at p16.3 and encodes the sulfate anion exchanger transporter 1 (SAT1) protein. The SAT1 protein is an anion exchanger protein that mediates exchange of negatively charged ions, including bicarbonate, chloride, oxalate, and sulfate, across the plasma membrane. The protein is expressed in multiple tissues, including in the kidney: there, it mediates renal tubular transmembrane anion exchange (Krick et al., 2009; PMID: 19369292), and thereby plays an important role in homeostasis of these ions. *SLC26A1* was first reported in association with calcium oxalate nephrolithiasis in 2013 (Dawson 2013 PMID: 24250268), with both heterozygous and homozygous variants noted. However, the first publication that reported *SLC26A1* in association with autosomal recessive calcium oxalate nephrolithiasis specifically was in 2016 (Gee 2016 PMID: 27210743); here, the disease mechanism was proposed to be loss-of-function. Calcium oxalate nephrolithiasis is characterized by formation of calcium oxalate stones in the kidneys due to supersaturation of the urine by the stone-forming constituents (i.e., calcium and oxalate). Patients may present asymptomatically, or with flank pain, hematuria, urinary tract infections, and/or acute renal failure due to urinary tract obstruction (by the stones). Laboratory analysis may show hypercalciuria and hyperoxaluria on 24-hour urine analysis. At least six unique variants across three publications have reported *SLC26A1* in association with calcium oxalate nephrolithiasis (Dawson 2013 PMID: 24250268, Gee 2016 PMID: 27210743, Wu 2016 PMID: 27125215). The variants reported are missense variants that are located throughout the protein. Several variants have supporting functional data supporting that they impair wild-type protein function, e.g., c.554C>T (p.Thr185Met) and c.1073C>T (p.Ser358Leu) (see Gee 2016 PMID: 27210743); however, for others, e.g., c.166G>A (p.Ala56Thr) and c.1667A>G (p.Gln556Arg), there is evidence suggesting that they do not impair wild-type protein function (Wu 2016 PMID: 27125215). There is also experimental evidence supporting the gene-disease association, including biochemical function (Krick 2009 PMID: 19369292) and expression data (Gee 2016, PMID: 27210743). There is also non-human model organism evidence; *SLC26A1* knockout mice showed a consistent phenotype, including hyperoxaluria, nephrocalcinosis, and calcium oxalate stones in the renal tubules and bladder (Dawson PA 2010, PMID: 20160351). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Tubulopathy GCEP on the meeting date 7/6/2022 (SOP Version 9).

Inheritance Pattern: AR

Disease ID:MONDO:0020722

Submitter: PanelApp Australia

Inheritance Pattern: AD

Disease ID:MONDO:0020722

Submitter: PanelApp Australia