NM_014140.4(SMARCAL1):c.1933C>T (p.Arg645Cys) AND Schimke immuno-osseous dysplasia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 5, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000004392.9

Allele description [Variation Report for NM_014140.4(SMARCAL1):c.1933C>T (p.Arg645Cys)]

NM_014140.4(SMARCAL1):c.1933C>T (p.Arg645Cys)

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_014140.4(SMARCAL1):c.1933C>T (p.Arg645Cys)

HGVS:

NC_000002.12:g.216450927C>T
NG_009771.1:g.43514C>T
NM_001127207.2:c.1933C>T
NM_014140.4:c.1933C>TMANE SELECT
NP_001120679.1:p.Arg645Cys
NP_054859.2:p.Arg645Cys
NP_054859.2:p.Arg645Cys
LRG_108t1:c.1933C>T
LRG_108:g.43514C>T
LRG_108p1:p.Arg645Cys
NC_000002.11:g.217315650C>T
NM_014140.3:c.1933C>T
Q9NZC9:p.Arg645Cys

Protein change:

R645C; ARG645CYS

Links:

UniProtKB: Q9NZC9#VAR_021375; OMIM: 606622.0005; dbSNP: rs119473037

NCBI 1000 Genomes Browser:

rs119473037

Molecular consequence:

NM_001127207.2:c.1933C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_014140.4:c.1933C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000024564	OMIM	no assertion criteria provided	Pathogenic (Feb 1, 2002)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000820568	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 5, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11799392, 22998683, 25748404, 18805831, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000024564

OMIM

no assertion criteria provided

Pathogenic
(Feb 1, 2002)

germline

literature only

PubMed (1)
[See all records that cite this PMID]

SCV000820568

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 5, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only

Citations

PubMed

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

Reduced elastogenesis: a clue to the arteriosclerosis and emphysematous changes in Schimke immuno-osseous dysplasia?

Morimoto M, Yu Z, Stenzel P, Clewing JM, Najafian B, Mayfield C, Hendson G, Weinkauf JG, Gormley AK, Parham DM, Ponniah U, André JL, Asakura Y, Basiratnia M, Bogdanović R, Bokenkamp A, Bonneau D, Buck A, Charrow J, Cochat P, Cordeiro I, Deschenes G, et al.

Orphanet J Rare Dis. 2012 Sep 22;7:70. doi: 10.1186/1750-1172-7-70.

PubMed [citation]

PMID:: 22998683
PMCID:: PMC3568709

See all PubMed Citations (5)

Details of each submission

From OMIM, SCV000024564.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

For discussion of the arg645-to-cys (R645C) mutation in the SMARCAL1 gene that was found in compound heterozygous state in a patient with relatively mild Schimke immunoosseous dysplasia (SIOD; 242900) by Boerkoel et al. (2002), see 606622.0004.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV000820568.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 645 of the SMARCAL1 protein (p.Arg645Cys). This variant is present in population databases (rs119473037, gnomAD 0.02%). This missense change has been observed in individuals with Schimke immuno-osseous dysplasia (PMID: 11799392, 22998683, 25748404). ClinVar contains an entry for this variant (Variation ID: 4175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SMARCAL1 protein function. Experimental studies have shown that this missense change affects SMARCAL1 function (PMID: 18805831). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 19, 2024

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