ClinVar Miner

Submissions for variant NM_014140.3(SMARCAL1):c.2114C>T (p.Thr705Ile) (rs200644381)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000778915 SCV000915325 uncertain significance Schimke immuno-osseous dysplasia 2017-09-13 criteria provided, single submitter clinical testing The SMARCAL1 c.2114C>T (p.Thr705Ile) missense variant has been reported in one study and is found one patient with Schimke immunoosseous dysplasia (SIOD) in a compound heterozygous state (Boerkoel et al. 2002). The patient is described as having a severe phenotype presenting with renal disease, lymphocytopenia, blood pancytopenia, central nervous symptoms, and died at 15 years old from a cerebrovascular event (Boerkoel et al. 2002). The p.Thr705Ile variant was absent from 252 control chromosomes and is reported at a frequency of 0.00035 in the European-American population of the Exome Sequencing Project. In vitro expression analysis showed reduced chromatin binding and complete nuclear localization of p.Thr705Ile, while expression in Drosophila melanogaster wings showed expression of two percent for p.Thr705Ile compared to 70% associated with wild type (Elizondo et al. 2009). Based on the evidence, the p.Thr705Ile variant is classified as a variant of unknown significance but suspicious for pathogenicity for Schimke immunoosseous dysplasia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
NIHR Bioresource Rare Diseases, University of Cambridge RCV001027620 SCV001190192 likely pathogenic Inherited Immunodeficiency Diseases 2019-01-01 criteria provided, single submitter research
Invitae RCV000778915 SCV001413762 uncertain significance Schimke immuno-osseous dysplasia 2020-10-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 705 of the SMARCAL1 protein (p.Thr705Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs200644381, ExAC 0.03%). This variant has been observed in individual(s) with Schimke immunoosseous dysplasia (SIOD) (PMID: 11799392, 30784191). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000778915 SCV001192581 pathogenic Schimke immuno-osseous dysplasia 2019-06-05 no assertion criteria provided clinical testing

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