This sequence change creates a premature translational stop signal (p.Asp474Glufs*2) in the ERCC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC3 are known to be pathogenic (PMID: 16947863). This variant is present in population databases (rs587778281, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosa (PMID: 16947863). ClinVar contains an entry for this variant (Variation ID: 134130). For these reasons, this variant has been classified as Pathogenic.
ClinVar Genomic variation as it relates to human health
NM_000122.2(ERCC3):c.1421dup (p.Asp474fs)
Germline
Classification
Help
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.
(10)
Help
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/Likely pathogenic
10
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_000122.2(ERCC3):c.1421dup (p.Asp474fs)
Variation ID: 134130 Accession: VCV000134130.44
- Type and length
-
Duplication, 1 bp
- Location
-
Cytogenetic: 2q14.3 2: 127280552-127280553 (GRCh38) [ NCBI UCSC ] 2: 128038128-128038129 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
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 Jun 9, 2014 Oct 20, 2024 May 1, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_000122.2:c.1421dup MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000113.1:p.Asp474fs frameshift NM_000122.1:c.1421dupA NM_001303416.2:c.1229dup NP_001290345.1:p.Asp410fs frameshift NM_001303418.2:c.1229dup NP_001290347.1:p.Asp410fs frameshift NC_000002.12:g.127280553dup NC_000002.11:g.128038129dup NG_007454.1:g.18624dup LRG_462:g.18624dup LRG_462t1:c.1421dup - Protein change
- D474fs, D410fs
- Other names
- -
- Canonical SPDI
- NC_000002.12:127280552:T:TT
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD) 0.00006
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD), exomes 0.00008
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00040
- Links
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 | ||
|---|---|---|---|---|---|---|
| HI score
Help
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. |
|||
| ERCC3 | - | - |
GRCh38 GRCh37 |
563 | 593 | |
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. |
|---|---|---|---|---|
| Pathogenic (2) |
criteria provided, single submitter
|
Oct 8, 2019 | RCV000018055.33 | |
| not provided (1) |
no classification provided
|
Sep 19, 2013 | RCV000120802.2 | |
| Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
May 1, 2024 | RCV000482017.33 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Feb 8, 2022 | RCV002477310.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Feb 23, 2022 | RCV002255296.3 | |
|
ERCC3-related disorder
|
Pathogenic (1) |
no assertion criteria provided
|
May 16, 2024 | RCV004757130.1 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(May 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004235169.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
|
|
|
Pathogenic
(Nov 15, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV002241342.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
This sequence change creates a premature translational stop signal (p.Asp474Glufs*2) in the ERCC3 gene. It is expected to result in an absent or disrupted protein … (more)
This sequence change creates a premature translational stop signal (p.Asp474Glufs*2) in the ERCC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC3 are known to be pathogenic (PMID: 16947863). This variant is present in population databases (rs587778281, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosa (PMID: 16947863). ClinVar contains an entry for this variant (Variation ID: 134130). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
Pathogenic
(Oct 08, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Xeroderma pigmentosum group B
Affected status: yes
Allele origin:
unknown
|
Centre for Mendelian Genomics, University Medical Centre Ljubljana
Accession: SCV001369260.2
First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020 |
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
|
|
|
Pathogenic
(Feb 23, 2022)
|
criteria provided, single submitter
Method: curation
|
Xeroderma pigmentosum
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002532598.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Comment:
The ERCC3 c.1421dupA (p.D474EfsX2) variant has been reported in individuals with xeroderma pigmentosum and Cockayne syndrome, sarcoma, melanoma and uterine carcinoma (PMID: 16947863, 29625052, 30414346). … (more)
The ERCC3 c.1421dupA (p.D474EfsX2) variant has been reported in individuals with xeroderma pigmentosum and Cockayne syndrome, sarcoma, melanoma and uterine carcinoma (PMID: 16947863, 29625052, 30414346). This variant causes a frameshift at amino acid 474 that results in premature termination 2 amino acids downstream. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Loss of function of the ERCC3 gene is an established disease mechanism in xeroderma pigmentosum group B (clinicalgenome.org). It was observed in 18/129082 chromosomes of the Non-Finnish European subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 134130). Based on the current evidence available, this variant is interpreted as pathogenic. (less)
|
|
|
|
Likely pathogenic
(Feb 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Xeroderma pigmentosum group B
Trichothiodystrophy 2, photosensitive
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV002778452.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
|
|
|
Likely pathogenic
(Nov 03, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000566524.6
First in ClinVar: Apr 27, 2017 Last updated: Nov 25, 2023 |
Comment:
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 … (more)
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; Also known as c.1421_1422insA; This variant is associated with the following publications: (PMID: 26971583, 27356891, 31589614, 30414346, 29625052, 34308104, 24728327, 36451132, 36493725, 16947863) (less)
|
|
|
Likely pathogenic
(May 01, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV001245707.26
First in ClinVar: May 12, 2020 Last updated: Oct 20, 2024 |
Comment:
ERCC3: PVS1, PM2:Supporting
Number of individuals with the variant: 2
|
|
|
Pathogenic
(Nov 01, 2006)
|
no assertion criteria provided
Method: literature only
|
XERODERMA PIGMENTOSUM B/COCKAYNE SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000038334.4
First in ClinVar: Apr 04, 2013 Last updated: Sep 24, 2022 |
Comment on evidence:
In a patient with a severe form of type B xeroderma pigmentosum/Cockayne syndrome (610651), Oh et al. (2006) identified compound heterozygosity for 2 mutations in … (more)
In a patient with a severe form of type B xeroderma pigmentosum/Cockayne syndrome (610651), Oh et al. (2006) identified compound heterozygosity for 2 mutations in the ERCC3 gene: a splice site mutation (133510.0001) and a 1-bp insertion (1421insA) in exon 9, resulting in a frameshift and premature termination of the protein at codon 475. (less)
|
|
|
Pathogenic
(May 16, 2024)
|
no assertion criteria provided
Method: clinical testing
|
ERCC3-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV005352961.1
First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024 |
Comment:
The ERCC3 c.1421dupA variant is predicted to result in a frameshift and premature protein termination (p.Asp474Glufs*2). This variant has been reported in an individual with … (more)
The ERCC3 c.1421dupA variant is predicted to result in a frameshift and premature protein termination (p.Asp474Glufs*2). This variant has been reported in an individual with xeroderma pigmentosum/Cockayne syndrome (Oh et al. 2006. PubMed ID: 16947863). This variant has also been reported in multiple individuals with various cancers including colorectal, endometrial, melanoma, and leukemia (Table 2, Dobbins et al. 2016. PubMed ID: 27356891; Table S1, Huang et al. 2018. PubMed ID: 29625052; Table 2, Potjer et al. 2019. PubMed ID: 30414346; Table S2, Kim et al. 2021. PubMed ID: 34308104). This variant is reported in 0.014% of alleles in individuals of European (non-Finnish) descent in gnomAD and it has been classified as pathogenic/likely pathogenic by other institutions in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/134130/). An in vitro experimental study suggests this variant affects DNA repair mechanisms (Figure 2, Oh et al. 2006. PubMed ID: 16947863). Frameshift variants in ERCC3 are expected to be pathogenic. This variant is interpreted as pathogenic. (less)
|
|
|
not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
|
AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000084966.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
|
Comment:
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Comment:
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; Also known as c.1421_1422insA; This variant is associated with the following publications: (PMID: 26971583, 27356891, 31589614, 30414346, 29625052, 34308104, 24728327, 36451132, 36493725, 16947863)
Comment:
ERCC3: PVS1, PM2:Supporting
Comment:
The ERCC3 c.1421dupA variant is predicted to result in a frameshift and premature protein termination (p.Asp474Glufs*2). This variant has been reported in an individual with xeroderma pigmentosum/Cockayne syndrome (Oh et al. 2006. PubMed ID: 16947863). This variant has also been reported in multiple individuals with various cancers including colorectal, endometrial, melanoma, and leukemia (Table 2, Dobbins et al. 2016. PubMed ID: 27356891; Table S1, Huang et al. 2018. PubMed ID: 29625052; Table 2, Potjer et al. 2019. PubMed ID: 30414346; Table S2, Kim et al. 2021. PubMed ID: 34308104). This variant is reported in 0.014% of alleles in individuals of European (non-Finnish) descent in gnomAD and it has been classified as pathogenic/likely pathogenic by other institutions in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/134130/). An in vitro experimental study suggests this variant affects DNA repair mechanisms (Figure 2, Oh et al. 2006. PubMed ID: 16947863). Frameshift variants in ERCC3 are expected to be pathogenic. This variant is interpreted as pathogenic.
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. |
Comment:
This sequence change creates a premature translational stop signal (p.Asp474Glufs*2) in the ERCC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ERCC3 are known to be pathogenic (PMID: 16947863). This variant is present in population databases (rs587778281, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with xeroderma pigmentosa (PMID: 16947863). ClinVar contains an entry for this variant (Variation ID: 134130). For these reasons, this variant has been classified as Pathogenic.
Comment:
This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Comment:
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; Also known as c.1421_1422insA; This variant is associated with the following publications: (PMID: 26971583, 27356891, 31589614, 30414346, 29625052, 34308104, 24728327, 36451132, 36493725, 16947863)
Comment:
ERCC3: PVS1, PM2:Supporting
Comment:
The ERCC3 c.1421dupA variant is predicted to result in a frameshift and premature protein termination (p.Asp474Glufs*2). This variant has been reported in an individual with xeroderma pigmentosum/Cockayne syndrome (Oh et al. 2006. PubMed ID: 16947863). This variant has also been reported in multiple individuals with various cancers including colorectal, endometrial, melanoma, and leukemia (Table 2, Dobbins et al. 2016. PubMed ID: 27356891; Table S1, Huang et al. 2018. PubMed ID: 29625052; Table 2, Potjer et al. 2019. PubMed ID: 30414346; Table S2, Kim et al. 2021. PubMed ID: 34308104). This variant is reported in 0.014% of alleles in individuals of European (non-Finnish) descent in gnomAD and it has been classified as pathogenic/likely pathogenic by other institutions in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/134130/). An in vitro experimental study suggests this variant affects DNA repair mechanisms (Figure 2, Oh et al. 2006. PubMed ID: 16947863). Frameshift variants in ERCC3 are expected to be pathogenic. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Multigene panel sequencing of established and candidate melanoma susceptibility genes in a large cohort of Dutch non-CDKN2A/CDK4 melanoma families. | Potjer TP | International journal of cancer | 2019 | PMID: 30414346 |
| Pathogenic Germline Variants in 10,389 Adult Cancers. | Huang KL | Cell | 2018 | PMID: 29625052 |
| Phenotypic heterogeneity in the XPB DNA helicase gene (ERCC3): xeroderma pigmentosum without and with Cockayne syndrome. | Oh KS | Human mutation | 2006 | PMID: 16947863 |
Text-mined citations for rs587778281 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 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.