Nephrocalcinosis or nephrolithiasis
Gene: SLC26A1
Based on previous reviews listed here, SLC26A1 has been rated as red for this panel - Nephrocalcinosis or nephrolithiasis.Created: 13 Feb 2024, 4:42 p.m. | Last Modified: 13 Feb 2024, 4:42 p.m.
Panel Version: 4.13
Report in 2023 of a patient with a homozygous variant in SLC26A1, as well as of pLoF variants in a CKD cohort found an association with urinary sulphate, but not oxalate excretion. I also have a personal communication from Felix Knauf, who was unable to confirm hyperoxaluria in the same mouse model (PMID: 20160351) that was originally reported as being hyperoxaluric. This is yet unpublished, but consistent with the paper by Whittamore et al., which was also unable to confirm hyperoxaluria in SLC26A1 ko mice.
Moreover, in the original paper reporting 2 patients with oxalate kidney stones and biallelic variants in SLC26A1 (PMID: 27210743), values for urinary oxalate excretion in the 2 patients are only provided in the supplement and are normal (49 mg/d/1.73m2) in one and only borderline elevated (58 mg/d/1.73m2) in the other patient, based on the reference range provided in the same table (<54.4 mg/d/1.73m2). Based on the usually used reference range (<45 mg/d/1.73m2) both patients are only borderline hyperoxaluric.
Thus, the role of SLC26A1 in oxalate excretion and nephrolithiasis is highly questionable.Created: 20 Jul 2023, 8:18 a.m. | Last Modified: 20 Jul 2023, 8:18 a.m.
Panel Version: 4.1
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
hyperoxaluria
Publications
Comment on list classification: Changing rating from grey to amber. Although there are several reported cases there is also evidence that the reported variants are not causative.Created: 25 Mar 2020, 5:45 p.m. | Last Modified: 25 Mar 2020, 5:45 p.m.
Panel Version: 2.6
Comment on list classification: Changing rating from grey to amber. Although there are several reported cases there is also evidence that the reported variants are not causative.Created: 25 Mar 2020, 5:45 p.m. | Last Modified: 25 Mar 2020, 5:45 p.m.
Panel Version: 2.5
Provisionally associated with ?Nephrolithiasis, calcium oxalate #167030 (AR) in OMIM.
PMID: 30383413 - Whittamore et al 2019 - were unable to reproduce the hyperoxaluria, hyperoxalemia, and urolithiasis of the original SAT-1-KO mouse model.
PMID: 27125215 - Wu et al 2016 - report that Human SLC26A1-mediated anion exchange differs from that of its rodent orthologs. Also using Xenopus oocytes they find that the C41W, A56T (also reported by Gee et al) variants found in a Mexican child with recessive proximal tubular Fanconi Syndrome and the Q566R and M132T variants from Dawson et al 2013 did not alter the functional properties tested of SLC26A1 and so the proposal that these are pathogenic variants for Renal Fanconi Syndrome disease or nephrolithiasis is NOT supported.
PMID: 27210743 - Gee et al 2016 - report 2 unrelated individuals. Case 1 - individual of Macedonian descent (A3054-21) who is from non-consanguineous parents and clinically presented with acute renal failure due to bilateral obstructive calculi, nephrocalcinosis, and bilateral ureteropelvic junction obstruction. Two compound heterozygous missense mutations (c.554C>T, p.Thr185Met and c.1073C>T, p.Ser358Leu) in SLC26A1 are reported. They have minor allele freq below 0.0006 in dbSNP. Case 2 - European-American boy (B641-12) who had nephrolithiasis and was born to consanguineous parents. A homozygous missense mutation (c.166G>A, p.Ala56Thr) in SLC26A1 was found. Its minor allele frequency is 0.0002 in dbSNP.
PMID: 24250268 - Dawson et al 2013 - screened the SLC26A1 gene in a cohort of 13 individuals with recurrent calcium oxalate urolithiasis. Found one individual was heterozygous R372H; 4 individuals were heterozygous Q556R; one patient was homozygous Q556R; and one patient with severe nephrocalcinosis (requiring nephrectomy) was homozygous Q556R and heterozygous M132T. The Q556R variant is found at a high allele frequency (0.3484 in NCBI).
PMID: 20160351 - Dawson et al 2010 - Sat1-/- mice (SLC26A1) exhibited hyperoxaluria with hyperoxalemia, nephrocalcinosis, and calcium oxalate stones in their renal tubules and bladder.
Summary:
Although there are 3+ cases (2 biallelic in Gee et al, 3 monalleleic and 2 biallelic in Dawson et al 2013), plus a mouse model (Dawson et all 2010), the high minor allele frequency of the Q556R variant and the lack of altered function in protein with the A56T and M132T variants (Wu et al), and the lack of reproducibility of the mouse model phenotype cast doubt on the causative role of these variants. Therefore this gene should be rated amber until more evidence for their role in nephrocalcinosis can be established.Created: 25 Mar 2020, 5:20 p.m. | Last Modified: 25 Mar 2020, 5:39 p.m.
Panel Version: 2.4
Three unrelated families and a mouse model.
Sources: Expert listCreated: 16 Jan 2020, 5:13 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Nephrolithiasis, calcium oxalate, MIM#167030
Publications
Variants in this GENE are reported as part of current diagnostic practice
Gene: slc26a1 has been classified as Red List (Low Evidence).
Publications for gene: SLC26A1 were set to 27210743; 20160351; 30383413; 27125215; 24250268
Publications for gene: SLC26A1 were set to 27210743; 20160351; 30383413; 27125215
Publications for gene: SLC26A1 were set to 27210743; 27210743; 20160351; 30383413; 27125215
Publications for gene: SLC26A1 were set to 27210743; 27210743; 20160351
Gene: slc26a1 has been classified as Amber List (Moderate Evidence).
Gene: slc26a1 has been classified as Amber List (Moderate Evidence).
gene: SLC26A1 was added gene: SLC26A1 was added to Nephrocalcinosis or nephrolithiasis. Sources: Expert list Mode of inheritance for gene: SLC26A1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: SLC26A1 were set to 27210743; 27210743; 20160351 Phenotypes for gene: SLC26A1 were set to Nephrolithiasis, calcium oxalate, MIM#167030 Review for gene: SLC26A1 was set to GREEN gene: SLC26A1 was marked as current diagnostic