ClinVar Genomic variation as it relates to human health

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

This missense ERCC4 variant at c.2395C>T (p.R799W) was seen on exome through the Texome project (R01HG011795). This variant has been described in individuals with ERCC4-related conditions (PMID: 8797827, 9579555, 20221251, 27528516). It has been observed in gnomAD with a frequency of 0.040% in the heterozygous state and has not been observed in the homozygous state (PM2). Functional studies suggest this variant is functionally defective (PMID: 9579555, 20221251) (PS3).This variant is predicted to be deleterious (CADD: 31.000) (PP3). The evolutionary conservation of this residue is high. We classify this variant as pathogenic.

The ERCC4 c.2395C>T (p.Arg799Trp) missense change has a maximum subpopulation frequency of 0.081% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/16-14041848-C-T). Six of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), and in vitro functional assays in LCLs (Epstein–Barr virus transformed lymphoblastoid cell lines) and fibroblasts have shown that this variant causes reduced protein expression of nuclear ERCC4 which is attributed to protein mislocalization and can result in decreased cell survival and DNA replication after ultraviolet light exposure (PS3; PMID: 20221251, 29105242, 9579555). This variant has been reported in over ten individuals affected with xeroderma pigmentosum (PS4, PM3; PMID: 8797827, 9579555, 23623389, 21228398, 28431612, 29892709). In addition, it has been reported in three individuals with autosomal recessive cerebellar ataxia with mild pigmentation of exposed skin areas and/or an equivocal history of pathological sunburn (PMID: 29403087), one individual with sporadic ataxia (PMID: 31692161), two individuals with head and neck squamous cell carcinoma (PMID: 28678401), one individual with sporadic pancreatic adenocarcinoma (PMID: 28767289), one individual with Cockayne syndrome (PMID: 29105242), and one individual with colorectal cancer (PMID: 31871297). This variant is also known as p.Arg788Trp in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied: PS3, PS4, PM3, PP3.

Published functional studies demonstrate R799W decreased activity compared to wild-type (Ahmad et al., 2010).; This variant is associated with the following publications: (PMID: 26074087, 20221251, 24728327, 9579555, 22941649, 23623386, 21612988, 23623389, 18628313, 28678401, 27356891, 29376097, 28376890, 8797827, 28767289, 28431612, 29403087, 27528516, 21228398, 29105242, 34426522, 30665703, 31692161, 31980526, 31871297, 29892709)

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 799 of the ERCC4 protein (p.Arg799Trp). This variant is present in population databases (rs121913049, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of ERCC4-related conditions (PMID: 8797827, 20221251, 23623389, 26074087, 27356891, 27528516, 28431612, 28678401, 28767289, 29105242, 29403087, 29892709). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.2377C>T, p.Arg788Trp. ClinVar contains an entry for this variant (Variation ID: 16580). 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: 9579555, 20221251). For these reasons, this variant has been classified as Pathogenic.

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.

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.

Variant summary: ERCC4 c.2395C>T (p.Arg799Trp) results in a non-conservative amino acid change located in the ERCC4 domain (IPR006166) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 251312 control chromosomes, predominantly at a frequency of 0.00089 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC4 causing Xeroderma Pigmentosum phenotype (0.00019), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin, although this could represent a higher carrier frequency in this population. c.2395C>T has been widely reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with mild features of Xeroderma Pigmentosum associated with later onset neurodegeneration/ataxia/chorea/variant forms of Cockayne syndrome/XP-F complementation group (example, Sijbers_1998, Ahmad_2010, Marelli_2016, Carre_2017, Ngo_2020, Kashiyama_2013, Shanbag_2018, Doi_2018, Mori_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Sijbers_1998, Ahmad_2010). The most pronounced variant effect results in approximately 20% of normal Nucleotide Excision Repair (NER) activity. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Pathogenic/Likely Pathogenic, n=8; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely pathogenic.

ERCC4 NM_005236 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.

ERCC4: PM3:Very Strong, PM2, PS3:Supporting

The ERCC4 c.2395C>T variant is predicted to result in the amino acid substitution p.Arg799Trp. This variant has been reported in the compound heterozygous and homozygous state in patients affected with xeroderma pigmentosum (F) (reported as R788W in Sijbers et al. 1996. PubMed ID: 8797827 and Sijbers et al. 1998. PubMed ID: 9579555; HGMD# CM960516 in Table S9 in Bell et al. 2011. PubMed ID: 21228398; Doi et al. 2018. PubMed ID: 29403087; Shanbhag et al. 2018. PubMed ID: 29892709; Marelli et al. 2016. PubMed ID: 27528516; Kashiyama et al. 2013. PubMed ID: 23623389).  This variant has also been identified in individuals with pancreatic adenocarcinoma (Shindo et al. 2017. PubMed ID: 28767289), head and neck squamous cell carcinoma (Chandrasekharappa et al. 2017. PubMed ID: 28678401), and colorectal cancer (Goldstein et al. 2020. PubMed ID: 31871297), but was also found in healthy control individuals (Table 2, Dobbins et al. 2016. PubMed ID: 27356891; Bodian et al. 2014. PubMed ID: 24728327).  In Dobbins et al. 2016 paper the authors conclude that they did not observe a significant difference in the frequency of pathogenic variants between cases and controls in their cohort. This variant is reported in 0.081% of alleles in individuals of European (non-Finnish) descent in gnomAD. Based on the available evidence, this variant is interpreted as likely pathogenic for autosomal recessive ERCC4-related disease.

Variant interpreted as Pathogenic and reported on 12-16-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.