Submissions for variant NM_005236.3(ERCC4):c.1765C>T (p.Arg589Trp)

dbSNP: rs147105770

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000049250	SCV000594580	likely pathogenic	Xeroderma pigmentosum, type F/Cockayne syndrome	2017-01-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000700109	SCV000828850	pathogenic	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2024-05-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 589 of the ERCC4 protein (p.Arg589Trp). This variant is present in population databases (rs147105770, gnomAD 0.02%). This missense change has been observed in individual(s) with xeroderma pigmentosa (PMID: 20221251, 21612988, 23623389, 26074087, 26884178, 29325523, 29892709). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 55829). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ERCC4 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ERCC4 function (PMID: 26453996, 30165384). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000762956	SCV000893393	pathogenic	Xeroderma pigmentosum, group F; XFE progeroid syndrome; Fanconi anemia complementation group Q	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222373	SCV002500097	pathogenic	Xeroderma pigmentosum	2022-03-04	criteria provided, single submitter	clinical testing	Variant summary: ERCC4 c.1765C>T (p.Arg589Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.4e-05 in 249106 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ERCC4 causing Xeroderma Pigmentosum (6.4e-05 vs 0.00019), allowing no conclusion about variant significance. The variant, c.1765C>T, has been reported in the literature in multiple individuals affected with Xeroderma Pigmentosum (e.g. Ahmad_2010, Gregg_2011, Manandhar_2015, Fassihi_2016, Shanbhag_2018) and some affected individuals also had Fanconi anemia, although with varying severity (e.g. Kashiyama_2013, Popp_2018). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated disrupted protein-protein interaction with SLX4 (Hashimoto_2015), mislocalization to the cytoplasm and strong hypersensitivity to UV and cross-linking agents in cells transfected with the variant protein (Sabatella_2018). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=1) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003415812	SCV004106108	pathogenic	ERCC4-related disorder	2023-01-09	criteria provided, single submitter	clinical testing	The ERCC4 c.1765C>T variant is predicted to result in the amino acid substitution p.Arg589Trp. This variant has been reported in the heterozygous state along with a second ERCC4 variant in individuals with autosomal recessive xeroderma pigmentosum type F, Cockayne syndrome, and Fanconi anemia (Table 1, Ahmad et al. 2010. PubMed ID: 20221251; Table 2, Kashiyama et al. 2013. PubMed ID: 23623389; Popp et al. 2018. PubMed ID: 29325523; Table 1, Shanbhag et al. 2018. PubMed ID: 29892709; Table 1, Sabatella et al. 2018. PubMed ID: 30165384). In vitro experimental studies suggest this variant impacts protein function (Table 1, Ahmad et al. 2010. PubMed ID: 20221251; Table 2, Kashiyama et al. 2013. PubMed ID: 23623389; Popp et al. 2018. PubMed ID: 29325523). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-14029554-C-T) and is interpreted as pathogenic and likely pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/55829/). This variant is interpreted as pathogenic.
OMIM	RCV000049250	SCV000077503	pathogenic	Xeroderma pigmentosum, type F/Cockayne syndrome	2013-05-02	no assertion criteria provided	literature only