NM_014140.3(SMARCAL1):c.2114C>T (p.Thr705Ile) AND Schimke immuno-osseous dysplasia

Clinical significance:Uncertain significance (Last evaluated: Oct 9, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000778915.4

Allele description [Variation Report for NM_014140.3(SMARCAL1):c.2114C>T (p.Thr705Ile)]

NM_014140.3(SMARCAL1):c.2114C>T (p.Thr705Ile)

Gene:
SMARCAL1:SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a like 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2q35
Genomic location:
Preferred name:
NM_014140.3(SMARCAL1):c.2114C>T (p.Thr705Ile)
HGVS:
  • NC_000002.12:g.216464640C>T
  • NG_009771.1:g.57227C>T
  • NM_001127207.2:c.2114C>T
  • NM_014140.3:c.2114C>T
  • NP_001120679.1:p.Thr705Ile
  • NP_054859.2:p.Thr705Ile
  • LRG_108t1:c.2114C>T
  • LRG_108:g.57227C>T
  • LRG_108p1:p.Thr705Ile
  • NC_000002.11:g.217329363C>T
Protein change:
T705I
Links:
dbSNP: rs200644381
NCBI 1000 Genomes Browser:
rs200644381
Molecular consequence:
  • NM_001127207.2:c.2114C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014140.3:c.2114C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Schimke immuno-osseous dysplasia (SIOD)
Synonyms:
Spondyloepiphyseal dysplasia nephrotic syndrome; Schimke syndrome; Schimke immunoosseous dysplasia
Identifiers:
MONDO: MONDO:0009458; MedGen: C0877024; Orphanet: 1830; OMIM: 242900

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000915325Illumina Clinical Services Laboratory,Illuminacriteria provided, single submitter
Uncertain significance
(Sep 13, 2017)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV001192581Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcareno assertion criteria providedPathogenic
(Jun 5, 2019)
germlineclinical testing

SCV001413762Invitaecriteria provided, single submitter
Uncertain significance
(Oct 9, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Schimke immuno-osseous dysplasia: SMARCAL1 loss-of-function and phenotypic correlation.

Elizondo LI, Cho KS, Zhang W, Yan J, Huang C, Huang Y, Choi K, Sloan EA, Deguchi K, Lou S, Baradaran-Heravi A, Takashima H, Lücke T, Quiocho FA, Boerkoel CF.

J Med Genet. 2009 Jan;46(1):49-59. doi: 10.1136/jmg.2008.060095. Epub 2008 Sep 19.

PubMed [citation]
PMID:
18805831

Mutant chromatin remodeling protein SMARCAL1 causes Schimke immuno-osseous dysplasia.

Boerkoel CF, Takashima H, John J, Yan J, Stankiewicz P, Rosenbarker L, André JL, Bogdanovic R, Burguet A, Cockfield S, Cordeiro I, Fründ S, Illies F, Joseph M, Kaitila I, Lama G, Loirat C, McLeod DR, Milford DV, Petty EM, Rodrigo F, Saraiva JM, et al.

Nat Genet. 2002 Feb;30(2):215-20. Epub 2002 Jan 22.

PubMed [citation]
PMID:
11799392
See all PubMed Citations (4)

Details of each submission

From Illumina Clinical Services Laboratory,Illumina, SCV000915325.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare, SCV001192581.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001413762.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 7, 2021

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