ClinVar Genomic variation as it relates to human health
NM_000124.4(ERCC6):c.2203C>T (p.Arg735Ter)
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000124.4(ERCC6):c.2203C>T (p.Arg735Ter)
Variation ID: 1701 Accession: VCV000001701.41
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 10q11.23 10: 49478437 (GRCh38) [ NCBI UCSC ] 10: 50686483 (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 May 9, 2015 Mar 10, 2024 Jan 11, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000124.4:c.2203C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000115.1:p.Arg735Ter nonsense NM_001346440.2:c.2203C>T NP_001333369.1:p.Arg735Ter nonsense NC_000010.11:g.49478437G>A NC_000010.10:g.50686483G>A NG_009442.1:g.65665C>T LRG_465:g.65665C>T LRG_465t1:c.2203C>T - Protein change
- R735*
- Other names
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- Canonical SPDI
- NC_000010.11:49478436:G:A
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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
Help
The frequency of the allele represented by this VCV record.
Trans-Omics for Precision Medicine (TOPMed) 0.00003
The Genome Aggregation Database (gnomAD) 0.00005
The Genome Aggregation Database (gnomAD), exomes 0.00007
Exome Aggregation Consortium (ExAC) 0.00009
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
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
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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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ERCC6 | - | - |
GRCh38 GRCh37 |
1502 | 1912 |
Conditions - Germline
Condition
Help
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
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
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 (2) |
no assertion criteria provided
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Mar 16, 2017 | RCV000001770.14 | |
Pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Jul 1, 2023 | RCV000001769.22 | |
Pathogenic (1) |
criteria provided, single submitter
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Apr 28, 2017 | RCV000406377.13 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 11, 2024 | RCV000521977.32 | |
Pathogenic (1) |
criteria provided, single submitter
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Mar 4, 2022 | RCV002476910.8 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 11, 2019 | RCV001199022.10 |
Submissions - Germline
Classification
Help
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
Help
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
Help
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
Help
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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Pathogenic
(Jan 09, 2012)
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criteria provided, single submitter
Method: clinical testing
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Cockayne syndrome, type B
(Autosomal recessive inheritance)
Affected status: not provided
Allele origin:
germline
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Claritas Genomics
Accession: SCV000222794.1
First in ClinVar: May 09, 2015 Last updated: May 09, 2015 |
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Pathogenic
(Feb 29, 2016)
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criteria provided, single submitter
Method: clinical testing
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Cockayne syndrome, type B
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000594582.1
First in ClinVar: Aug 28, 2017 Last updated: Aug 28, 2017 |
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Pathogenic
(Apr 28, 2017)
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criteria provided, single submitter
Method: clinical testing
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ERCC6-Related Disorders
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000362890.3
First in ClinVar: Dec 06, 2016 Last updated: May 24, 2019 |
Comment:
The ERCC6 c.2203C>T (p.Arg735Ter) variant is a stop-gained variant predicted to result in permature termination of the protein. The p.Arg735Ter variant has been reported in … (more)
The ERCC6 c.2203C>T (p.Arg735Ter) variant is a stop-gained variant predicted to result in permature termination of the protein. The p.Arg735Ter variant has been reported in at least three studies in which it is found in a total of five patients, including one homozygote and two compound heterozygotes with Cockayne syndrome, and two homozygotes with de Sanctis-Cacchione syndrome (Mallery et al. 1998; Colella et al. 2000; Laugel et al. 2010). Control data are unavailable for this variant which is reported at a frequency of 0.00015 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies using primary fibroblast cell lines derived from patients with the p.Arg735Ter variant showed that the variant was associated with defective telomere maintenance as well as increased reactive oxygen species and mitochondrial oxidative stress but was not associated with nuclear DNA damage (Batenburg et al. 2012; Cleaver et al. 2014). Functional studies of induced pluripotent stem cells derived from skin fibroblasts carrying the p.Arg735Ter variant also showed that the lack of functional CSB protein caused by the variant did not prevent genetic reprogramming but did increase cell death and reactive oxygen species production (Andrade et al. 2012). Further, in a telomerase-immortalized cell line carrying the p.Arg375Ter variant in a homozygous state, addition of wild type CSB showed a significant decrease in the amount of cells with IR-induced 53BP1 foci and a significantly increased amount of cells with cyclin A and IR-induced foci of BRCA1, RPA, and Rad51, suggesting there is defective homologous recombination-mediated double strand break repair (Batenburg et al. 2015). Based on the collective evidence and the potential impact of stop-gained variants, the p.Arg275Ter variant is classified as pathogenic for ERCC6-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. (less)
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Pathogenic
(Apr 07, 2020)
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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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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001474159.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
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Pathogenic
(Nov 03, 2019)
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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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Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV001714947.1
First in ClinVar: Jun 15, 2021 Last updated: Jun 15, 2021 |
Comment:
PVS1, PS3, PS4_moderate, PM2, PM3, PP4
Number of individuals with the variant: 1
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Pathogenic
(Jul 01, 2023)
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criteria provided, single submitter
Method: research
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Cockayne syndrome type 2
Affected status: yes
Allele origin:
paternal
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DECIPHERD-UDD, Universidad del Desarrollo
Accession: SCV004171011.1
First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024 |
Clinical Features:
Short stature (present) , Secondary microcephaly (present) , Global developmental delay (present) , Neonatal hypotonia (present) , Enlarged posterior fossa (present) , Epicanthus (present) , … (more)
Short stature (present) , Secondary microcephaly (present) , Global developmental delay (present) , Neonatal hypotonia (present) , Enlarged posterior fossa (present) , Epicanthus (present) , Anteverted nares (present) , Abnormal foot morphology (present) , Hernia (present) (less)
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Pathogenic
(Apr 08, 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: SCV002022208.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 11, 2024)
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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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Invitae
Accession: SCV000937297.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg735*) in the ERCC6 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Arg735*) in the ERCC6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC6 are known to be pathogenic (PMID: 18628313, 29572252). This variant is present in population databases (rs121917901, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome (PMID: 9443879). ClinVar contains an entry for this variant (Variation ID: 1701). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Feb 11, 2019)
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criteria provided, single submitter
Method: clinical testing
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Cerebrooculofacioskeletal syndrome 1
Affected status: yes
Allele origin:
unknown
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Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001370017.2
First in ClinVar: Jul 04, 2020 Last updated: Jul 04, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
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Pathogenic
(Mar 04, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cockayne syndrome type 2
Lung cancer Cerebrooculofacioskeletal syndrome 1 DE SANCTIS-CACCHIONE SYNDROME UV-sensitive syndrome 1 Age related macular degeneration 5 Premature ovarian failure 11
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893161.2
First in ClinVar: Mar 31, 2019 Last updated: Dec 31, 2022 |
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Pathogenic
(Jun 17, 2022)
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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: SCV000617667.5
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more)
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 9443879, 28687971, 30111349, 32257569, 31589614) (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001954277.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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Pathogenic
(May 01, 2000)
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no assertion criteria provided
Method: literature only
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COCKAYNE SYNDROME B
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021925.3
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
In a Turkish patient with Cockayne syndrome B (CSB; 133540) and consanguineous parents, Mallery et al. (1998) identified a homozygous 2282C-T transition in the ERCC6 … (more)
In a Turkish patient with Cockayne syndrome B (CSB; 133540) and consanguineous parents, Mallery et al. (1998) identified a homozygous 2282C-T transition in the ERCC6 gene, resulting in an arg735-to-ter (R735X) substitution. This same truncating mutation was found in compound heterozygous state with an arg453-to-ter (R453X; 609413.0004) mutation in another patient studied by Mallery et al. (1998). Colella et al. (2000) demonstrated homozygosity for the R735X mutation in the ERCC6 gene in 2 sibs with de Sanctis-Cacchione syndrome (278800), a form of xeroderma pigmentosum associated with severe neurologic involvement. The authors concluded that there is no simple correlation between molecular defects in Cockayne syndrome B and clinical features, and that other genetic and/or environmental factors may determine the pathologic phenotype. (less)
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Pathogenic
(May 01, 2000)
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no assertion criteria provided
Method: literature only
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DE SANCTIS-CACCHIONE SYNDROME
Affected status: not provided
Allele origin:
germline
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OMIM
Accession: SCV000021926.4
First in ClinVar: Apr 04, 2013 Last updated: Oct 23, 2016 |
Comment on evidence:
In a Turkish patient with Cockayne syndrome B (CSB; 133540) and consanguineous parents, Mallery et al. (1998) identified a homozygous 2282C-T transition in the ERCC6 … (more)
In a Turkish patient with Cockayne syndrome B (CSB; 133540) and consanguineous parents, Mallery et al. (1998) identified a homozygous 2282C-T transition in the ERCC6 gene, resulting in an arg735-to-ter (R735X) substitution. This same truncating mutation was found in compound heterozygous state with an arg453-to-ter (R453X; 609413.0004) mutation in another patient studied by Mallery et al. (1998). Colella et al. (2000) demonstrated homozygosity for the R735X mutation in the ERCC6 gene in 2 sibs with de Sanctis-Cacchione syndrome (278800), a form of xeroderma pigmentosum associated with severe neurologic involvement. The authors concluded that there is no simple correlation between molecular defects in Cockayne syndrome B and clinical features, and that other genetic and/or environmental factors may determine the pathologic phenotype. (less)
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Pathogenic
(Mar 16, 2017)
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no assertion criteria provided
Method: clinical testing
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DE SANCTIS-CACCHIONE SYNDROME
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000790360.2
First in ClinVar: Aug 05, 2018 Last updated: Dec 23, 2019 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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Cockayne syndrome type 2
Affected status: yes
Allele origin:
germline
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Genomics England Pilot Project, Genomics England
Accession: SCV001760252.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001976212.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
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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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Decoding complex inherited phenotypes in rare disorders: the DECIPHERD initiative for rare undiagnosed diseases in Chile. | Poli MC | European journal of human genetics : EJHG | 2024 | PMID: 38177409 |
Encephalopathies with intracranial calcification in children: clinical and genetic characterization. | Tonduti D | Orphanet journal of rare diseases | 2018 | PMID: 30111349 |
Functional and clinical relevance of novel mutations in a large cohort of patients with Cockayne syndrome. | Calmels N | Journal of medical genetics | 2018 | PMID: 29572252 |
Cockayne syndrome group B protein regulates DNA double-strand break repair and checkpoint activation. | Batenburg NL | The EMBO journal | 2015 | PMID: 25820262 |
Mitochondrial reactive oxygen species are scavenged by Cockayne syndrome B protein in human fibroblasts without nuclear DNA damage. | Cleaver JE | Proceedings of the National Academy of Sciences of the United States of America | 2014 | PMID: 25136123 |
Cockayne Syndrome group B protein interacts with TRF2 and regulates telomere length and stability. | Batenburg NL | Nucleic acids research | 2012 | PMID: 22904069 |
Evidence for premature aging due to oxidative stress in iPSCs from Cockayne syndrome. | Andrade LN | Human molecular genetics | 2012 | PMID: 22661500 |
Mutation update for the CSB/ERCC6 and CSA/ERCC8 genes involved in Cockayne syndrome. | Laugel V | Human mutation | 2010 | PMID: 19894250 |
Cerebro-oculo-facio-skeletal syndrome: three additional cases with CSB mutations, new diagnostic criteria and an approach to investigation. | Laugel V | Journal of medical genetics | 2008 | PMID: 18628313 |
Identical mutations in the CSB gene associated with either Cockayne syndrome or the DeSanctis-cacchione variant of xeroderma pigmentosum. | Colella S | Human molecular genetics | 2000 | PMID: 10767341 |
Molecular analysis of mutations in the CSB (ERCC6) gene in patients with Cockayne syndrome. | Mallery DL | American journal of human genetics | 1998 | PMID: 9443879 |
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Text-mined citations for rs121917901 ...
HelpRecord last updated Apr 15, 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.