SMARCAL1

Inheritance Pattern: AR

Disease ID:MONDO:0009458

Submitter: ClinGen

The SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1 (SMARCAL1) gene is located on chromosome 2q35 and encodes an ATP-dependent helicase that binds DNA forks and is involved with stability, restarting stalled replication forks, and DNA damage response. The SMARCAL1 gene was first reported in relation to autosomal recessive Schimke immune-osseous dysplasia (SIOD) in 2002 (Boerkoel et al., PMID 11799392). At least 13 unique variants (nonsense, frameshift, splice, missense) have been reported in humans. Diagnostic features include spondyloepiphyseal dysplasia, renal dysfunction, lymphocytopenia and/or T-cell immunodeficiency. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least eight probands in at least four publications (Bétous et al., 2002, PMID 11799392; Dekel et al., 2008, PMID 18356746; Liu et al., 2017, PMID 29282041; Jin et al., 2019, PMID 31275356). Variants were reported in unaffected carrier parents and were not identified in additional affected family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is supported by a zebrafish model that recapitulates phenotype (Huang et al., 2010, PMID 20036229) and in vitro rescue studies in patient fibroblasts (Bansbach et al., 2010, 21327070). In summary, ​SMARCAL1​​ is definitively associated with autosomal recessive Schimke immune-osseous dysplasia. 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 Syndromic Disorders Gene Curation Expert Panel on the meeting date 19Feb2021 (SOP Version 8).

Inheritance Pattern: AD

Disease ID:MONDO:1060247

Submitter: ClinGen

SMARCAL1 was first linked to autosomal recessive Schimke immuno-osseous dysplasia (SIOD) in 2002 (Boerkoel et al., PMID: 11799392). SMARCAL1 has been more recently reported in association with autosomal dominant SMARCAL1-related tumor predisposition in 2020 (Akhavanfard et al., PMID: 32371905). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in molecular mechanism, but a difference in inheritance pattern and phenotypic variability was found. Therefore, the following disease entities have been split into multiple disease entities, Schimke immuno-osseous dysplasia (SIOD) (OMIM: 606622) and SMARCAL1-related tumor predisposition. The split curation autosomal recessive Schimke immuno-osseous dysplasia (SIOD) was previously curated separately. Two case-control studies with 2,349 individuals with osteosarcoma are included in this curation (PMIDs: 41066719, 40996338). Oak et al., an aggregate variant analysis, showed an odds ratio of 6.3, 95% CI = 2.5 to 13.6, p<0.0001 for osteosarcoma compared to non-cancer controls (PMID: 41066719). Rafati et al., an aggregate variant analysis, showed an odds ratio of 5.4, 95% CI = 2.5 to 11.5, p<0.0001 for osteosarcoma compared to cancer-free individuals in the European subset of data (PMID: 40996338). In addition to case-control studies, 12 variants (missense, nonsense, frameshift, splice site) that have been reported in 15 probands (8 with osteosarcoma and 7 with other cancers including sarcoma, glioma, gastrointestinal stromal tumor (GIST) and malignancies of the nervous system) in 2 publications (PMIDs: 32371905, 36656928) and in ClinVar (ClinVar IDs: 645077 (Accession: SCV007596980.1), 577921(Accession: SCV007596982.1), 4851566 (Accession: SCV007596981.1)) are included in this curation. No experimental evidence that supports this gene-disease relationship was found, and therefore none was included in this curation. The mechanism of pathogenicity appears to be loss of function, but it is unclear due to the lack of experimental evidence. In summary, there is strong evidence supporting the relationship between SMARCAL1 and autosomal dominant SMARCAL1-related tumor predisposition. This has been repeatedly demonstrated in clinical genetic data, and but has not been upheld over time since both case-control studies were published in 2025. This classification was approved by the ClinGen Childhood, Adolescent and Young Adult Cancer Predisposition (CAYA) GCEP on the meeting date June 10, 2026 (SOP Version 12).

Inheritance Pattern: AR

Disease ID:MONDO:0009458

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0009458

Submitter: Natera

Inheritance Pattern: AR

Disease ID:MONDO:0009458

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0009458

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0009458

Submitter: Labcorp Genetics (formerly Invitae)