ClinVar Miner

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

gnomAD frequency: 0.00007  dbSNP: rs587778281
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482017 SCV000566524 likely pathogenic not provided 2023-11-03 criteria provided, single submitter clinical testing 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)
CeGaT Center for Human Genetics Tuebingen RCV000482017 SCV001245707 likely pathogenic not provided 2025-04-01 criteria provided, single submitter clinical testing ERCC3: PVS1, PM2:Supporting
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000018055 SCV001369260 pathogenic Xeroderma pigmentosum group B 2019-10-08 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
Labcorp Genetics (formerly Invitae), Labcorp RCV000482017 SCV002241342 pathogenic not provided 2024-05-14 criteria provided, single submitter clinical testing 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.
Sema4, Sema4 RCV002255296 SCV002532598 pathogenic Xeroderma pigmentosum 2022-02-23 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002477310 SCV002778452 likely pathogenic Xeroderma pigmentosum group B; Trichothiodystrophy 2, photosensitive 2022-02-08 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000482017 SCV004235169 pathogenic not provided 2023-05-25 criteria provided, single submitter clinical testing
OMIM RCV000018055 SCV000038334 pathogenic Xeroderma pigmentosum group B 2006-11-01 no assertion criteria provided literature only
ITMI RCV000120802 SCV000084966 not provided not specified 2013-09-19 no assertion provided reference population
PreventionGenetics, part of Exact Sciences RCV004757130 SCV005352961 pathogenic ERCC3-related disorder 2024-05-16 no assertion criteria provided clinical testing 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.

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