ClinVar Miner

Submissions for variant NM_005236.2(ERCC4):c.2395C>T (p.Arg799Trp) (rs121913049)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
CeGaT Praxis fuer Humangenetik Tuebingen RCV000415873 SCV000493482 uncertain significance not provided 2016-07-31 criteria provided, single submitter clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768209 SCV000898673 uncertain significance Xeroderma pigmentosum, group F; XFE progeroid syndrome; Fanconi anemia, complementation group Q 2017-09-18 criteria provided, single submitter clinical testing ERCC4 NM_005236.2 exon 11 p.Arg799Trp (c.2395C>T): This variant has been reported in the literature in at least 5 individuals with features or a diagnosis of Xeroderma Pigmentosum-F as compound heterozygous or homozygous (Sijbers 1996 PMID: 8797827, Sijbers 1998 PMID:9579555, Kashiyama 2013 PMID:23623389, Marelli 2016 PMID:27528516, Carre 2017 PMID:28431612). This variant is present in 103/126562 Caucasian individuals in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs121913049). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population and/or variable expressivity. This variant is present in ClinVar (Variation ID:16580). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In addition, functional studies have shown a deleterious effect of this variant (Sijbers 1998 PMID:9579555, de Laat 1998 PMID:9722633). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
ITMI RCV000120808 SCV000084973 not provided not specified 2013-09-19 no assertion provided reference population
Illumina Clinical Services Laboratory,Illumina RCV000018048 SCV000914705 pathogenic Xeroderma pigmentosum, group F 2018-12-19 criteria provided, single submitter clinical testing Across a selection of the available literature, the ERCC4 c.2395C>T (p.Arg799Trp) variant has been identified in 11 probands with xeroderma pigmentosum including five in a homozygous state, four in a heterozygous state and two in a compound heterozygous state (Sijbers et al. 1996; Sijbers et al. 1998; Gregg et al. 2011). The p.Arg799Trp variant is reported at a frequency of 0.001 in the European American population of the Exome Sequencing Project. Functional rescue studies showed that the variant could only partially rescue the nuclear excision repair defect and that the variant protein mislocalized to the cytoplasm (Sijbers et al. 1998; Ahmad et al. 2010). Based on the collective evidence, the p.Arg799Trp variant is classified as pathogenic for xeroderma pigmentosum. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Invitae RCV000467658 SCV000548332 uncertain significance Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia, complementation group Q 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 799 of the ERCC4 protein (p.Arg799Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs121913049, ExAC 0.08%). This variant has been reported in individuals affected with xeroderma pigmentosum including in individuals homozygous for this variant (PMID: 8797827, 23623389, 26074087, 20221251), and individuals affected with familial colorectal cancer, pancreatic ductal adenocarcinoma, head and neck squamous cell carcinoma, cerebellar atrophy, inherited cerebellar ataxia, and segmental progeroid syndrome (PMID: 27356891, 28767289, 28678401, 28431612, 27528516, 29105242). This variant is also known as c.2377C>T, p.Arg788Trp in the literature. ClinVar contains an entry for this variant (Variation ID: 16580). Experimental studies regarding the effect of this variant on catalytic function have produced conflicting results (PMID: 20221251, 9579555). Fibroblast cells from homozygous individuals for this variant were shown to be deficient in ERCC4 protein and showed moderately reduced cell survival and DNA replication after exposure to ultraviolet light (PMID: 23623389, 9579555). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000120808 SCV000539115 uncertain significance not specified 2016-03-29 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Present in 1/908 alleles in the other population and in 55/66734 European alleles of ExAC. Reported by Sijbers_1996 in a compound heterozygous individual with XP group F.
OMIM RCV000018048 SCV000038327 pathogenic Xeroderma pigmentosum, group F 1998-05-01 no assertion criteria provided literature only
OMIM RCV000766208 SCV000897688 pathogenic XFE progeroid syndrome 2019-04-04 no assertion criteria provided literature only

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