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

gnomAD frequency: 0.00007  dbSNP: rs587778281

Total submissions: 10

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.