NM_006265.3(RAD21):c.1753T>C (p.Cys585Arg) AND Cornelia de Lange syndrome 4

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Sep 17, 2021
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000029139.18

Allele description [Variation Report for NM_006265.3(RAD21):c.1753T>C (p.Cys585Arg)]

NM_006265.3(RAD21):c.1753T>C (p.Cys585Arg)

Gene:

RAD21:RAD21 cohesin complex component [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

8q24.11

Genomic location:

Preferred name:

NM_006265.3(RAD21):c.1753T>C (p.Cys585Arg)

Other names:

C585R

HGVS:

NC_000008.11:g.116847643A>G
NG_032862.1:g.32224T>C
NM_006265.3:c.1753T>CMANE SELECT
NP_006256.1:p.Cys585Arg
LRG_772t1:c.1753T>C
LRG_772:g.32224T>C
LRG_772p1:p.Cys585Arg
NC_000008.10:g.117859882A>G
NM_006265.2:c.1753T>C
O60216:p.Cys585Arg

Protein change:

CYS585ARG

Links:

UniProtKB: O60216#VAR_068692; OMIM: 606462.0002; dbSNP: rs387907213

NCBI 1000 Genomes Browser:

rs387907213

Molecular consequence:

NM_006265.3:c.1753T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Cornelia de Lange syndrome 4 (CDLS4)
Synonyms:: CORNELIA DE LANGE SYNDROME 4 WITH OR WITHOUT MIDLINE BRAIN DEFECTS
Identifiers:: MONDO: MONDO:0013864; MedGen: C3553517; Orphanet: 199; OMIM: 614701

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000050589	OMIM	no assertion criteria provided	Pathogenic (Jun 8, 2012)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV000262560	GeneReviews	no classification provided	not provided	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001573015	Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 22, 2020)	de novo	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002243381	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Sep 17, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22633399, 32193685, 28492532

Help

Summary from all submissions

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

RAD21 mutations cause a human cohesinopathy.

Deardorff MA, Wilde JJ, Albrecht M, Dickinson E, Tennstedt S, Braunholz D, Mönnich M, Yan Y, Xu W, Gil-Rodríguez MC, Clark D, Hakonarson H, Halbach S, Michelis LD, Rampuria A, Rossier E, Spranger S, Van Maldergem L, Lynch SA, Gillessen-Kaesbach G, Lüdecke HJ, Ramsay RG, et al.

Am J Hum Genet. 2012 Jun 8;90(6):1014-27. doi: 10.1016/j.ajhg.2012.04.019. Epub 2012 May 24.

PubMed [citation]

PMID:: 22633399
PMCID:: PMC3370273

See all PubMed Citations (4)

Details of each submission

From OMIM, SCV000050589.2

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

Description

In a girl with Cornelia de Lange syndrome-4 (CDLS4; 614701), Deardorff et al. (2012) identified a de novo heterozygous 1753T-C transition in the RAD21 gene, resulting in a cys585-to-arg (C585R) substitution in a residue conserved in vertebrates. The mutation was not found in 600 control chromosomes. Structural modeling suggested that the C585R mutation is within the C terminus of RAD21 positioned near the interface of RAD21 and the C-terminal residues of SMC1 (300040), and may interfere with the interaction between these 2 cohesion proteins, causing a defect in formation of functional cohesin complexes. The patient had microcephaly and a characteristic facial appearance, with thick, bushy, arched eyebrows, synophrys, long eyelashes, broad nasal bridge, smooth philtrum, thin upper lip, short nose, and upslanted palpebral fissures. Other features included short fingers, fifth finger clinodactyly, small prominent first toe, long fourth metacarpal, cutis marmorata, and mild neurodevelopmental defects. Zebrafish C597R (corresponding to human C585R) failed to rescue Runx1 expression in Rad21-null embryos and showed only background levels of activity in wildtype embryos, consistent with a loss of function.

#	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 GeneReviews, SCV000262560.2

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

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

From Genomic Medicine Lab, University of California San Francisco - CSER-P3EGS, SCV001573015.1

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

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002243381.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects RAD21 function (PMID: 22633399). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 35460). This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 22633399, 32193685; external communication). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 585 of the RAD21 protein (p.Cys585Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.

#	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: Nov 10, 2024

ClinVar

Relating variation to medicine