ClinVar Genomic variation as it relates to human health
NM_006265.3(RAD21):c.1753T>C (p.Cys585Arg)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic(2); Likely pathogenic(1); Uncertain significance(1)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_006265.3(RAD21):c.1753T>C (p.Cys585Arg)
Variation ID: 35460 Accession: VCV000035460.11
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8q24.11 8: 116847643 (GRCh38) [ NCBI UCSC ] 8: 117859882 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Feb 2, 2016 Feb 14, 2024 Feb 2, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_006265.3:c.1753T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_006256.1:p.Cys585Arg missense NC_000008.11:g.116847643A>G NC_000008.10:g.117859882A>G NG_032862.1:g.32224T>C LRG_772:g.32224T>C LRG_772t1:c.1753T>C LRG_772p1:p.Cys585Arg O60216:p.Cys585Arg - Protein change
- Other names
- C585R
- Canonical SPDI
- NC_000008.11:116847642:A:G
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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RAD21 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
353 | 414 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 17, 2021 | RCV000029139.17 | |
Conflicting interpretations of pathogenicity (2) |
criteria provided, conflicting classifications
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Feb 2, 2023 | RCV003133119.12 |
Submissions - Germline
Classification
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The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
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The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
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The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Feb 02, 2023)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV004023983.1
First in ClinVar: Aug 13, 2023 Last updated: Aug 13, 2023 |
Comment:
Reported in a family with Cornelia de Lange syndrome; however, information about parental testing was not provided (Krab et al., 2020); Not observed at significant … (more)
Reported in a family with Cornelia de Lange syndrome; however, information about parental testing was not provided (Krab et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32687945, 22633399, 25575569, 23882154, 30125677, 27882533, 20301283, 24038889, 32193685, 30716475) (less)
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Uncertain significance
(Feb 22, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV003810462.2
First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024 |
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Pathogenic
(Sep 17, 2021)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 4
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002243381.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
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Pathogenic
(Oct 22, 2020)
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criteria provided, single submitter
Method: clinical testing
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Cornelia de Lange syndrome 4
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Genomic Medicine Lab, University of California San Francisco
Study: CSER-P3EGS
Accession: SCV001573015.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021 |
Sex: male
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Pathogenic
(Jun 08, 2012)
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no assertion criteria provided
Method: literature only
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CORNELIA DE LANGE SYNDROME 4
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000050589.2
First in ClinVar: Apr 04, 2013 Last updated: Sep 09, 2018 |
Comment on evidence:
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, … (more)
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. (less)
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not provided
(-)
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no classification provided
Method: literature only
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Cornelia de Lange syndrome 4
Affected status: yes
Allele origin:
germline
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GeneReviews
Accession: SCV000262560.2
First in ClinVar: Feb 02, 2016 Last updated: Oct 01, 2022 |
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Germline Functional Evidence
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 germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Delineation of phenotypes and genotypes related to cohesin structural protein RAD21. | Krab LC | Human genetics | 2020 | PMID: 32193685 |
Cornelia de Lange Syndrome. | Adam MP | - | 2020 | PMID: 20301283 |
RAD21 mutations cause a human cohesinopathy. | Deardorff MA | American journal of human genetics | 2012 | PMID: 22633399 |
Text-mined citations for rs387907213 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.