SLC34A1

Inheritance Pattern: AR

Disease ID:MONDO:0013247

Submitter: ClinGen

The *SLC34A1* gene is located on chromosome 5 at q35.3 and encodes the Solute Carrier Family 34 Member 1. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their molecular mechanism, inheritance pattern and phenotypic spectrum. Therefore, Fanconi renotubular syndrome 2 (OMIM:613388) has been split from the following disease entities, Hypercalcemia, infantile, 2 (OMIM: 616963), and Nephrolithiasis/osteoporosis, hypophosphatemic, 1 (OMIM:612286). The lumped disease entity for autosomal recessive hypercalcemia, infantile, 2 and autosomal dominant nephrolithiasis/osteoporosis, hypophosphatemic, 1 has been curated separately. *SLC34A1* was first reported in relation to autosomal recessive Fanconi renotubular syndrome 2 in 2010 (Magen et al., PMID: 20335586). The mechanism of pathogenicity is reported to be loss of function. Fanconi renotubular syndrome is a renal disorder resulting from decreased solute and water reabsorption in the proximal tubule of the kidney. Only one variant (in-frame duplication) has been reported in one proband in one publication (PMID: 20335586, included in this curation). A total of 0.5/12 pts. for genetic evidence was reached considering case-level data. There is very little evidence supporting this gene-disease association beyond the expression of SLC34A1 in the brush border of proximal tubule cells in humans (PMID: 8327470). A total of 0.5/6 pts. for experimental evidence was reached. In summary, the evidence supporting the relationship between *SLC34A1* and autosomal recessive Fanconi renotubular syndrome 2 has been disputed and no valid evidence remains to support the claim. More evidence is needed to either support or entirely refute the role SLC34A1 plays in this disease. This gene-disease pair was originally evaluated by the Tubulopathy GCEP on 09/06/2022 (SOP Version 9). It was reevaluated on 12/03/2025 (SOP Version 11). As a result of this reevaluation, the classification did not change, as no new genetic or experimental evidence was found.

Inheritance Pattern: AD

Disease ID:MONDO:0012850

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014851

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0012850

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0007600

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013247

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AD

Disease ID:MONDO:0012850

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0007749

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014851

Submitter: ClinGen

The *SLC34A1* gene is located on chromosome 5 at q35.3 and encodes the Solute Carrier Family 34 Member 1. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was evidence of differences in their molecular mechanism, inheritance pattern and phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: Hypercalcemia, infantile, 2 (OMIM: 616963) and Nephrolithiasis/osteoporosis, hypophosphatemic, 1 (OMIM:612286), and split from Fanconi renotubular syndrome 2 (OMIM:613388). The preferred disease name suggested for this lumped autosomal recessive disorder is ‘Infantile hypercalcemia - *SLC34A1*’. Heterozygous carriers of pathogenic variants are at an increased risk of developing nephrolithiasis, as associated with autosomal dominant hypophosphatemic nephrolithiasis/osteoporosis 1. Autosomal recessive Fanconi renotubular syndrome 2 has been curated separately. *SLC34A1* was first reported in relation to autosomal recessive infantile hypercalcemia in 2014 (Rajagopal et al., PMID: 25050900). The mechanism of pathogenicity is known to be loss of function. Infantile hypercalcemia is characterized by severe hypercalcemia, with failure to thrive, vomiting, dehydration, and nephrocalcinosis. At least 15 variants (missense, deletions, nonsense, frameshift, and splice site) have been reported in 10 probands in 3 publications (PMIDs: 25050900, 26047794, 30943683 included in this curation). Of note, the c.272_292del (p.Val91_Ala97del) variant included in this curation is a noted polymorphism that can be causative of disease when inherited in trans with another pathogenic variant. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease association is also supported by mouse models phenocopying disease in human patients, expression studies at the brush border of proximal tubule cells in humans, biochemical function critical to actively transporting phosphate into cells via Na+ cotransport, and functional alteration demonstrating multiple variants are unable to produce Pi uptakes comparable to the wild type (PMIDs: 8327470, 9560283, 20335586, 26047794). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) has been reached. In summary, there is definitive evidence supporting the relationship between SLC34A1 and autosomal recessive infantile hypercalcemia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

Inheritance Pattern: AD

Disease ID:MONDO:0016579

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0014851

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014851

Submitter: Labcorp Genetics (formerly Invitae)