Submission Details

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.