ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.1846C>T (p.Arg616Trp)

gnomAD frequency: 0.00004  dbSNP: rs121913024
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001582486 SCV001818743 pathogenic not provided 2024-10-02 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: R616W results in absent binding and transcriptional activity of TFIIH (PMID: 12820975); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22234153, 26344056, 22617342, 9238033, 11734544, 34426522, 31589614, 36259739, 7920640, 7585650, 23800062, 24252196, 11443545, 12820975)
Revvity Omics, Revvity RCV001582486 SCV002024502 likely pathogenic not provided 2019-04-05 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001582486 SCV002125364 pathogenic not provided 2024-12-18 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 616 of the ERCC2 protein (p.Arg616Trp). This variant is present in population databases (rs121913024, gnomAD 0.01%). This missense change has been observed in individuals with ERCC2-related conditions (PMID: 9238033, 11443545, 22234153, 27396511). This variant is also known as XPD. ClinVar contains an entry for this variant (Variation ID: 16788). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ERCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ERCC2 function (PMID: 25431422). This variant disrupts the p.Arg616 amino acid residue in ERCC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7920640, 9238033, 11734544, 23221806, 23800062). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002468972 SCV002766025 pathogenic Xeroderma pigmentosum 2022-11-08 criteria provided, single submitter clinical testing Variant summary: ERCC2 c.1846C>T (p.Arg616Trp) results in a non-conservative amino acid change located in the ATP-dependent helicase, C-terminal domain (IPR006555) of 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 5.6e-05 in 250884 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ERCC2 causing Xeroderma Pigmentosum (5.6e-05 vs 0.00061), allowing no conclusion about variant significance. c.1846C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with features of Xeroderma Pigmentosum (XP), trichothiodystrophy (TTD) and Cerebro-oculo-facio skeletal (COFS) syndrome (example, Graham_2001, Queille_2001, Viprakasit_2001, Moslehi_2012). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Dubaele_2003). The most pronounced variant effect results in abolishment of interaction with the p44 subunit of TFIIH and an inhibition of basal transcription activity. 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics RCV000171547 SCV004194619 pathogenic Cerebrooculofacioskeletal syndrome 2 2023-12-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005016278 SCV005648392 pathogenic Cerebrooculofacioskeletal syndrome 2; Xeroderma pigmentosum, group D; Trichothiodystrophy 1, photosensitive 2024-03-10 criteria provided, single submitter clinical testing
OMIM RCV000018278 SCV000038557 pathogenic Xeroderma pigmentosum, group D 2001-08-01 no assertion criteria provided literature only
OMIM RCV000171547 SCV000223723 pathogenic Cerebrooculofacioskeletal syndrome 2 2001-08-01 no assertion criteria provided literature only

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