SLC41A1

Inheritance Pattern: AR

Disease ID:MONDO:0859175

Submitter: PanelApp Australia

Inheritance Pattern: Unknown

Disease ID:MONDO:0859175

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0005240

Submitter: ClinGen

*SLC41A1* was first reported in relation to an autosomal recessive kidney disease in 2013 (Hurd et al., PMID: 23661805). *SLC41A1* was associated with a kidney disease phenotype clinically, sonographically and histologically compatible with infantile nephronophthisis. In addition, respiratory symptoms and bronchiectasis have been reported in the 2 patients. At the time of this curation, there were no other single-gene disorders associated with this gene (other than ?Nephronophthisis-like nephropathy 2 (OMIM:619468)). Therefore, this assessment is based on this disease entity only and has been curated for *SLC41A1*-kidney disorder (MONDO:0005240). Only 1 single nucleotide variant that has been reported in homozygosity in 2 affected individuals from 1 consanguineous family in 1 publication (PMID: 23661805) is included in this curation. This acceptor splice site variant (c.698G>T) in *SLC41A1* has been shown to lead to skipping of exon 6 and an in-frame deletion of a transmembrane helix, with reduced protein expression and functional consequences. No other patients affected with *SLC41A1*-kidney disorder have been reported since 2013. The mechanism of pathogenicity is unknown as there is no described link between the function of SLC41A1 (magnesium transport) and the development of nephronophthisis. This gene-disease association is supported by limited experimental evidence including human kidney expression data and a morpholino-induced knockdown zebrafish model presenting with features compatible with a primary ciliopathy (PMID: 23661805). Of note, another study investigating morpholino-induced knockdown of *slc41a1* in zebrafish did not replicate the phenotypic features (PMID: 30417250). It is also noteworthy, that the 2 patients described with biallelic *SLC41A1* variants did not present with altered magnesium homeostasis and that a first cousin shared some clinical features (bronchiectasis) but was heterozygous for the family mutation (PMID: 23661805). In summary, there is limited evidence to support this gene-disease relationship that has not been replicated since 2013. Although more evidence is needed to support a causal role, no convincing human evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on the meeting date 05/11/22 (SOP Version 8).