SCLT1

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

The *SCLT1* gene is located in chromosome 4q28.2 and encodes the Sodium Channel And Clathrin Linker 1 protein. The protein is required for ciliogenesis and ciliary vesicle formation. It is ubiquitously expressed at varying levels in all tissues. Although no disease assertion has been made in the OMIM datase, variants in *SCLT1* have been reported in individuals with the following disease entities: Oral-facial-digital syndrome IX, retinitis pigmentosa, Senior-Loken syndrome, and Bardet-Biedl syndrome. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no differences in phenotypic variability. Therefore, these disease entities have been lumped into one disease entity. The preferred disease name suggested for this disorder is autosomal recessive ciliopathy-*SCLT1*. *SCLT1* was first reported in relation to autosomal recessive ciliopathy in 2014 (Adly et al., PMID: 24285566). The mechanism of pathogenicity appears to be loss-of-function. Patients with biallelic *SCLT1* variants presented with cystic kidney disease, nephronophthisis, orofacial cleft, genital anomalies, neurodevelopmental delay, intellectual disability, retinitis pigmentosa, and hepatic dysfunction. At least seven variants (canonical splice site, missense, splice site, indel) reported in five probands in five publications (PMID: 24285566, 30425282, 32253632, 37246745, 38924217) are included in this curation. There was functional evidence supporting the effect of the missense and splice site variants (PMID: 24285566, 30425282, 32253632, 37246745, 38924217). A total of 6.5 pts. for genetic evidence was reached. This gene-disease relationship is also supported by biochemical function, expression studies, functional alteration in non-patient cells, and animal models (PMID: 23348840, 36407107, 30425282, 39696441, 28486600). SCLT1 protein expression was observed in the tubule cells of the adult mouse kidney and the SCLT1 signal is observed at the basal part of the photoreceptor ciliary axoneme and the distal part of the basal body (PMID: 30425282). It was found that another ciliopathy gene, *CEP164*, depends on *SCLT1* for centriolar localization; disruption of Sclt1 in mesenchymal cells prevents the recruitment of CEP164 to the basal body (PMID: 23348840, 36407107). Depletion of *SCLT1* in RPE1 cells completely blocked cilia formation; similarly, NIH3T3 cells depleted of SCLT1 showed reduced anchoring of the cilium to the plasma membrane, indicating disrupted early ciliogenesis (PMID: 23348840, 39696441). Additionally, SCLT1 deficiency in knockout mouse embryos and mice results in a classic ciliopathy phenotype characterized by polydactyly, cleft palate, cystic kidneys, and shortened intestines (PMID: 28486600, 36407107). More evidence is available in the literature, but the maximum score for experimental evidence (6 pts.) was reached. In summary, there is definitive evidence supporting the relationship for *SCLT1* that we are terming autosomal recessive ciliopathy-*SCLT1*. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders Expert Panel GCEP on the meeting date December 8, 2025 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: LiferaOmics

Genetic evidence – Published PMID: 32253632 – Family 1 – one proband (compound heterozygous; non-consanguineous). Case-level (biallelic non-LOF in AR model; compound heterozygous; non-LOF start = 0.1; each variant evaluated independently; no consanguinity deduction) = 0.2; Segregation = 0; Case-control = 0 Family 1 total = 0.2 PMID: 32253632 – Family 2 – one proband (compound heterozygous; non-consanguineous). Case-level (biallelic non-LOF in AR model; compound heterozygous; non-LOF start = 0.1; each variant evaluated independently; no consanguinity deduction) = 0.2; Segregation = 0; Case-control = 0 Family 2 total = 0.2 PMID: 32253632 total = 0.4 PMID: 37644014 – Family 1 – one proband (homozygous; consanguinity not reported). Case-level (biallelic non-LOF in AR model; homozygous in-frame deletion; non-LOF start = 0.1) = 0.1; Segregation = 0; Case-control = 0 Family 1 total = 0.1 PMID: 37644014 total = 0.1 Published genetic evidence total = 0.5 / 12 Genetic evidence – Our cases Family 1 – one proband. Case-level (biallelic predicted null in AR model; homozygous c.290+2T>C; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 1 total = 1.0 Family 2 – one proband. Case-level (biallelic predicted null in AR model; homozygous c.290+2T>C; consanguinity −0.5 applied) = (1.5 − 0.5) = 1.0; Segregation = 0; Case-control = 0 Family 2 total = 1.0 Family 3 – one proband. Case-level (biallelic predicted null in AR model; homozygous c.290+2T>C; consanguinity not reported; conservative adjustment due to alternative SRY mosaicism explanation) = 1.0; Segregation = 0; Case-control = 0 Family 3 total = 1.0 Our cases total = 3.0 / 12 Total genetic evidence (published AR + our cases) Published genetic evidence: 0.5 Our additional cases: 3.0 Total genetic evidence = 3.5 / 12 Experimental evidence – Published PMID: 32253632 – Functional alteration (patient RNA; exon 14 skipping demonstrated) = 1.0 Gene function / biological plausibility (SCLT1 is a distal appendage protein required for ciliogenesis; disruption consistent with ciliopathy/BBS mechanism) = 0.5 No animal model or rescue data available for SCLT1–BBS at this time. Experimental evidence total = 1.5 / 6 Overall score Genetic evidence = 3.5 Experimental evidence = 1.5 Overall score = 5.0 / 18

Inheritance Pattern: AR

Disease ID:MONDO:0017842

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0019200

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: Franklin by Genoox

Two unrelated Japanese patients with clinical diagnoses of BBS associated with compound heterozygous SCLT1 mutation. Both paitents showed retinitis pigmentosa.