ClinVar Genomic variation as it relates to human health
NM_000124.4(ERCC6):c.3952_3953del (p.Arg1318fs)
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.3952_3953del (p.Arg1318fs)
Variation ID: 190171 Accession: VCV000190171.13
- Type and length
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Deletion, 2 bp
- Location
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Cytogenetic: 10q11.23 10: 49461382-49461383 (GRCh38) [ NCBI UCSC ] 10: 50669428-50669429 (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 Feb 20, 2024 Oct 29, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000124.4:c.3952_3953del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000115.1:p.Arg1318fs frameshift NM_000124.4:c.3952_3953delAG MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000124.2:c.3952_3953delAG NM_000124.3:c.3952_3953del NM_001346440.2:c.3952_3953del NP_001333369.1:p.Arg1318fs frameshift NC_000010.11:g.49461382_49461383del NC_000010.10:g.50669428_50669429del NG_009442.1:g.82719_82720del LRG_465:g.82719_82720del LRG_465t1:c.3952_3953del - Protein change
- R1318fs
- Other names
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- Canonical SPDI
- NC_000010.11:49461381:CT:
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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.
The Genome Aggregation Database (gnomAD) 0.00001
The Genome Aggregation Database (gnomAD), exomes 0.00002
Trans-Omics for Precision Medicine (TOPMed) 0.00002
Exome Aggregation Consortium (ExAC) 0.00001
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
Help
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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Likely pathogenic (1) |
criteria provided, single submitter
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Oct 22, 2013 | RCV000170390.1 | |
Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Apr 10, 2017 | RCV000666483.2 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 29, 2023 | RCV001231998.10 | |
Pathogenic (1) |
criteria provided, single submitter
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Jun 23, 2022 | RCV002271445.1 |
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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Likely pathogenic
(Oct 22, 2013)
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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: SCV000222810.1
First in ClinVar: May 09, 2015 Last updated: May 09, 2015 |
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Likely pathogenic
(Apr 10, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cockayne syndrome type 2
Cerebrooculofacioskeletal syndrome 1 DE SANCTIS-CACCHIONE SYNDROME
Affected status: unknown
Allele origin:
unknown
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Counsyl
Accession: SCV000790787.1
First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018 |
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Likely pathogenic
(-)
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criteria provided, single submitter
Method: research
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DE SANCTIS-CACCHIONE SYNDROME
Cockayne syndrome B Cerebrooculofacioskeletal syndrome 1
Affected status: no
Allele origin:
germline
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UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill
Study: NSIGHT-NC NEXUS
Accession: SCV001251489.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020 |
Comment:
The c.3952_3953delAG (p.R1318Gfs) variant is a frameshift deletion of two nucleotides predicted to result in a nonfunctional ERCC6 protein.
Number of individuals with the variant: 1
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Pathogenic
(Jun 23, 2022)
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criteria provided, single submitter
Method: clinical testing
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Cockayne syndrome
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV002556093.1
First in ClinVar: Aug 03, 2022 Last updated: Aug 03, 2022 |
Comment:
Variant summary: ERCC6 c.3952_3953delAG (p.Arg1318GlyfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein … (more)
Variant summary: ERCC6 c.3952_3953delAG (p.Arg1318GlyfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar database. The variant allele was found at a frequency of 2e-05 in 251212 control chromosomes (gnomAD). c.3952_3953delAG has been reported in the literature in two individuals affected with Cockayne Syndrome (Calmels_2018), one individual with clinical diagnosis and family history of hearing loss, loss of ambulation, hypotonia, cerebellar ataxia and sensory neuropathy (Monies_2019), one individual affected with acute lymphoblastic leukemia (Qin_2020) and one individual affected with malignant peritoneal mesothelioma (Hung_2020). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(Jan 18, 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: SCV001983862.4
First in ClinVar: Oct 30, 2021 Last updated: Nov 11, 2023 |
Comment:
Reported in two unrelated patients with Cockayne syndrome who each harbored another variant in the ERCC6 gene in published literature (Calmels et al., 2018); Identified … (more)
Reported in two unrelated patients with Cockayne syndrome who each harbored another variant in the ERCC6 gene in published literature (Calmels et al., 2018); Identified in a patient with a clinical diagnosis and family history of hearing loss, loss of ambulation, hypotonia, cerebellar ataxia and sensory neuropathy who underwent exome sequencing (Monies et al., 2019); this individual also harbored an intronic variant in ERCC6 though its clinical significance was considered to be unknown; Frameshift 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: 31130284, 29572252, 18628313, 9443879) (less)
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Pathogenic
(Oct 29, 2023)
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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: SCV001404539.5
First in ClinVar: Jul 16, 2020 Last updated: Feb 20, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Arg1318Glyfs*12) 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.Arg1318Glyfs*12) 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 (rs765825423, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Cockayne syndrome type B (PMID: 29572252). ClinVar contains an entry for this variant (Variation ID: 190171). For these reasons, this variant has been classified as Pathogenic. (less)
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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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Genomic Sequencing for Newborn Screening: Results of the NC NEXUS Project. | Roman TS | American journal of human genetics | 2020 | PMID: 32853555 |
Molecular characterization of diffuse malignant peritoneal mesothelioma. | Hung YP | Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | 2020 | PMID: 32504035 |
Pathogenic Germline Mutations in DNA Repair Genes in Combination With Cancer Treatment Exposures and Risk of Subsequent Neoplasms Among Long-Term Survivors of Childhood Cancer. | Qin N | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2020 | PMID: 32496904 |
Cockayne Syndrome: The many challenges and approaches to understand a multifaceted disease. | Vessoni AT | Genetics and molecular biology | 2020 | PMID: 32453336 |
Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population. | Monies D | American journal of human genetics | 2019 | PMID: 31130284 |
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 |
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 |
Text-mined citations for rs765825423 ...
HelpRecord last updated Feb 28, 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.