Mendeliome
Gene: SLC26A1 Red List (low evidence)Red List (low evidence)
1x hom 22yo, hom for p.(Leu275Pro).
Markedly lower plasma sulphate compared to controls
patient had a mean fractional excretion index (FEI) of sulphate of 24% when plasma sulphate was severely depressed indicated urinary sulphate wasting with inappropriately high fractional sulphate excretion in the urine. Twenty-four-hour urine collections for oxalate excretion revealed urinary oxalate values between 21.8 and 48.6 mg/ day (mean 33.7 mg/day), i.e., normal to only mildly elevated
Functional in Xenopus Oocytes show a reduction in cell surface expression.Created: 1 Jun 2023, 1:20 a.m. | Last Modified: 1 Jun 2023, 1:20 a.m.
Panel Version: 1.895
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
perichondritis, hyposulphatemia, renal sulphate wasting
Publications
Variants in this GENE are reported as part of current diagnostic practice
Red List (low evidence)
ClinGen Tubulopathy GCEP meeting 07/07/22 - gene disease association disputed, with the following factors cited:
- Associated phenotypes in the literature not consistent (nephrolithiasis not always reported, once reported in conjunction with nephrotic syndrome and in another instance with proximal Faconi renotubular syndrome - with each of these phenotypes involving different parts of the renal tubule/glomeruli)
- x1 convincing mouse model, but functional studies in humans not convincing
- Published variants prevalent in population database including instance of reported compound het variants being prevalent as compound het in gnomAD (identified through reviewing variant co-occurence) - c.554C>T (p.Thr185Met) and c.1073C>T (p.Ser358Leu)Created: 7 Jul 2022, 1:28 a.m. | Last Modified: 7 Jul 2022, 1:28 a.m.
Panel Version: 1.89
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
?Nephrolithiasis, calcium oxalate - MIM#167030
I don't know
Conflicting evidence for gene-disease association:
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.Created: 9 Sep 2021, 6:51 a.m. | Last Modified: 9 Sep 2021, 6:51 a.m.
Panel Version: 0.9121
Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Phenotypes
Nephrolithiasis, calcium oxalate, MIM#167030
Publications
Tag disputed tag was added to gene: SLC26A1.
Gene: slc26a1 has been classified as Red List (Low Evidence).
Gene: slc26a1 has been classified as Amber List (Moderate Evidence).
Phenotypes for gene: SLC26A1 were changed from to Nephrolithiasis, calcium oxalate, MIM#167030
Publications for gene: SLC26A1 were set to
Mode of inheritance for gene: SLC26A1 was changed from Unknown to BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Gene: slc26a1 has been classified as Amber List (Moderate Evidence).
gene: SLC26A1 was added gene: SLC26A1 was added to Mendeliome_VCGS. Sources: Expert Review Green,Victorian Clinical Genetics Services Mode of inheritance for gene: SLC26A1 was set to Unknown
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at panelapp@genomicsengland.co.uk
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.