VCV000134130.57 - ClinVar

NM_000122.2(ERCC3):c.1421dup (p.Asp474fs)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic/Likely pathogenic

7 out of 10 submissions contributed to this classification

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.

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: VCV000134130.57

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	Mar 7, 2026	Dec 30, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_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

... more HGVS ... less HGVS

Protein change

D474fs, D410fs

Other names

Canonical SPDI

NC_000002.12:127280552:T:TT

Global minor allele frequency (GMAF) Help The 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) 0.00007

The Genome Aggregation Database (gnomAD), exomes 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00010

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00040

Links

ClinGen: CA158854 OMIM: 133510.0006 dbSNP: rs587778281 VarSome

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
Gene	OMIM	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		Gene associated with autosomal recessive phenotype	No evidence available	GRCh38 GRCh37	687	718

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.
Xeroderma pigmentosum group B	Pathogenic (2)	criteria provided, single submitter	Oct 8, 2019	RCV000018055.33
not specified	not provided (1)	no classification provided	Sep 19, 2013	RCV000120802.2
not provided	Pathogenic/Likely pathogenic (4)	criteria provided, multiple submitters, no conflicts	Dec 30, 2025	RCV000482017.46
Xeroderma pigmentosum	Pathogenic (1)	criteria provided, single submitter	Feb 23, 2022	RCV002255296.3
Trichothiodystrophy 2, photosensitive Xeroderma pigmentosum group B	Likely pathogenic (1)	criteria provided, single submitter	Feb 8, 2022	RCV002477310.2
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.	Expand all rows Collapse all rows 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 (Oct 08, 2019) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Xeroderma pigmentosum group B	Centre for Mendelian Genomics, University Medical Centre Ljubljana Accession: SCV001369260.2 First in ClinVar: Jul 04, 2020 Last updated: Dec 12, 2020	Comment: show This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. (less) Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: yes Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: yes

Likely pathogenic (Feb 08, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Xeroderma pigmentosum group B Trichothiodystrophy 2, photosensitive	Fulgent Genetics, Fulgent Genetics Accession: SCV002778452.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Likely pathogenic (Nov 03, 2023) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000566524.6 First in ClinVar: Apr 27, 2017 Last updated: Nov 25, 2023	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (May 25, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	not provided	Revvity Omics, Revvity Accession: SCV004235169.2 First in ClinVar: Feb 04, 2024 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Dec 30, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	not provided	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002241342.5 First in ClinVar: Mar 28, 2022 Last updated: Mar 07, 2026	Publications: PubMed (1) PubMed: 16947863 Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Feb 23, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines)	Xeroderma pigmentosum	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)	Publications: PubMed (3) PubMed: 16947863‚ 29625052‚ 30414346 Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Likely pathogenic (Oct 01, 2025) C Contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV001245707.36 First in ClinVar: May 12, 2020 Last updated: Jan 11, 2026	Comment: show ERCC3: PVS1, PM2:Supporting (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 4

Pathogenic (Nov 01, 2006) N Not contributing to aggregate classification	no assertion criteria provided	XERODERMA PIGMENTOSUM B/COCKAYNE SYNDROME	OMIM Accession: SCV000038334.4 First in ClinVar: Apr 04, 2013 Last updated: Sep 24, 2022	Publications: PubMed (1) PubMed: 16947863 Observation: 1 Collection method: literature only Allele origin: germline Affected status: not provided more Observation 1 Collection method: literature only Allele origin: germline Affected status: not provided 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) N Not contributing to aggregate classification	no assertion criteria provided	ERCC3-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV005352961.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

not provided (Sep 19, 2013) N Not contributing to aggregate classification	no classification provided	AllHighlyPenetrant	ITMI Accession: SCV000084966.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation: 7 Observation 1 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Whole_cohort Platform type: next-gen sequencing Platform name: Complete Genomics Observation 2 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: African Platform type: next-gen sequencing Platform name: Complete Genomics Observation 3 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: African_European Platform type: next-gen sequencing Platform name: Complete Genomics Observation 4 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Central_Asian Platform type: next-gen sequencing Platform name: Complete Genomics Observation 5 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: East_Asian Platform type: next-gen sequencing Platform name: Complete Genomics Observation 6 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: European Platform type: next-gen sequencing Platform name: Complete Genomics Observation 7 Collection method: reference population Allele origin: germline Affected status: unknown Ethnicity/Population group: Hispanic Platform Type: next-gen sequencing Platform Name: Complete Genomics

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:

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:

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

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 ...

These 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 Mar 08, 2026