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

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely pathogenic(1);Pathogenic(1);Uncertain significance(2)

Review status:
criteria provided, conflicting interpretations
Submissions:
5 (Most recent: Sep 1, 2021)
Last evaluated:
Oct 9, 2020
Accession:
VCV000632064.8
Variation ID:
632064
Description:
single nucleotide variant
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NM_014140.4(SMARCAL1):c.2114C>T (p.Thr705Ile)

Allele ID
620059
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
2q35
Genomic location
2: 216464640 (GRCh38) GRCh38 UCSC
2: 217329363 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
LRG_108:g.57227C>T
LRG_108t1:c.2114C>T LRG_108p1:p.Thr705Ile
NC_000002.11:g.217329363C>T
... more HGVS
Protein change
T705I
Other names
-
Canonical SPDI
NC_000002.12:216464639:C:T
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
Trans-Omics for Precision Medicine (TOPMed) 0.00018
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
The Genome Aggregation Database (gnomAD), exomes 0.00010
Exome Aggregation Consortium (ExAC) 0.00011
The Genome Aggregation Database (gnomAD) 0.00019
Links
dbSNP: rs200644381
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 3 criteria provided, multiple submitters, no conflicts Oct 9, 2020 RCV000778915.4
Likely pathogenic 1 criteria provided, single submitter Jan 1, 2019 RCV001027620.1
Pathogenic 1 criteria provided, single submitter Jul 21, 2020 RCV001592958.3

Clinical features observed in individuals with this variant

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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
SMARCAL1 - - GRCh38
GRCh37
465 488

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Sep 13, 2017)
criteria provided, single submitter
Method: clinical testing
Schimke immuno-osseous dysplasia
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000915325.1
Submitted: (Feb 01, 2019)
Evidence details
Publications
PubMed (2)
Comment:
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 … (more)
Likely pathogenic
(Jan 01, 2019)
criteria provided, single submitter
Method: research
Inherited Immunodeficiency Diseases
Allele origin: germline
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001190192.1
Submitted: (Sep 30, 2019)
Evidence details
Uncertain significance
(Oct 09, 2020)
criteria provided, single submitter
Method: clinical testing
Schimke immuno-osseous dysplasia
Allele origin: germline
Invitae
Accession: SCV001413762.2
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (2)
Comment:
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 … (more)
Pathogenic
(Jul 21, 2020)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV001816268.1
Submitted: (Sep 01, 2021)
Evidence details
Comment:
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; … (more)
Pathogenic
(Jun 05, 2019)
no assertion criteria provided
Method: clinical testing
Schimke immuno-osseous dysplasia
Allele origin: germline
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare
Accession: SCV001192581.1
Submitted: (Mar 06, 2020)
Evidence details

Functional evidence

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There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Citations for this variant

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Title Author Journal Year Link
Klippel-Feil syndrome as a novel feature of Schimke immunoosseous dysplasia. Power BD American journal of medical genetics. Part A 2019 PMID: 30784191
Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation. Elizondo LI Journal of medical genetics 2009 PMID: 18805831
Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia. Boerkoel CF Nature genetics 2002 PMID: 11799392

Text-mined citations for rs200644381...

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These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 24, 2021