Submissions for variant NM_014140.4(SMARCAL1):c.2114C>T (p.Thr705Ile)

gnomAD frequency: 0.00019  dbSNP: rs200644381

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001027620	SCV001190192	likely pathogenic	Inherited Immunodeficiency Diseases	2019-01-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000778915	SCV001413762	likely pathogenic	Schimke immuno-osseous dysplasia	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 705 of the SMARCAL1 protein (p.Thr705Ile). This variant is present in population databases (rs200644381, gnomAD 0.02%). This missense change has been observed in individual(s) with Schimke immunoosseous dysplasia (PMID: 11799392, 30784191). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 632064). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SMARCAL1 protein function with a positive predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001592958	SCV001816268	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (Elizondo et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 11799392, 28780565, 28796785, 27577878, 30784191, 18805831, 32499645, 32581362, 34746741)
PreventionGenetics, part of Exact Sciences	RCV003413568	SCV004113989	pathogenic	SMARCAL1-related disorder	2023-02-03	criteria provided, single submitter	clinical testing	The SMARCAL1 c.2114C>T variant is predicted to result in the amino acid substitution p.Thr705Ile. This variant has been reported in the compound heterozygous and homozygous state in individuals with Schimke immuno-osseous dysplasia (Figure E6, Table E1, Stray-Pedersen et al. 2016. PubMed ID: 27577878; Power et al 2019. PubMed ID: 30784191; Boerkoel et al. 2002. PubMed ID: 11799392). This variant is reported in 0.020% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-217329363-C-T). This variant is interpreted as pathogenic.
Molecular Diagnostics Lab, Nemours Children's Health, Delaware	RCV004773137	SCV005382637	likely pathogenic	Focal segmental glomerulosclerosis	2024-09-13	criteria provided, single submitter	clinical testing	This missense vaiant (c.2144C>T, p.Thr705Ile) has been observed at extremely low frequency in population databases (gnomAD). It has been reported in the literature (PMID 18805821, 11799392, 30784191). Variant prediction programs suggest a deleterious effect, and functional studies support this. It was identified in an affected patient.
Fulgent Genetics, Fulgent Genetics	RCV000778915	SCV005648204	pathogenic	Schimke immuno-osseous dysplasia	2024-01-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000778915	SCV000915325	uncertain significance	Schimke immuno-osseous dysplasia	2017-09-13	flagged submission	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.
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000778915	SCV001192581	pathogenic	Schimke immuno-osseous dysplasia	2019-06-05	no assertion criteria provided	clinical testing