ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.776G>A (p.Cys259Tyr)

gnomAD frequency: 0.00004  dbSNP: rs370454709
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000349442 SCV000413584 likely pathogenic ERCC2-related disorder 2024-06-11 criteria provided, single submitter clinical testing
GeneDx RCV000435999 SCV000517252 likely pathogenic not provided 2022-01-11 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: destabilized protein, impaired DNA unwinding activity, decreased MAT1/ERCC2 interaction, reduced TFIIH activity, impaired TFIIH transcription initiation, and impaired TFIIH nucleotide excision repair activity (Botta et al., 2002; Liu et al., 2008; Orioli et al., 2013; Abdulrahman et al., 2013); 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: 26957611, 27085493, 23221806, 9758621, 12393803, 18510925, 23382212)
Sema4, Sema4 RCV002256206 SCV002531609 likely pathogenic Xeroderma pigmentosum 2021-12-13 criteria provided, single submitter curation
Labcorp Genetics (formerly Invitae), Labcorp RCV000435999 SCV003300779 likely pathogenic not provided 2023-11-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 259 of the ERCC2 protein (p.Cys259Tyr). This variant is present in population databases (rs370454709, gnomAD 0.01%). This missense change has been observed in individual(s) with trichothiodystrophy (PMID: 9758621). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 329522). 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 ERCC2 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ERCC2 function (PMID: 23382212). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Baylor Genetics RCV003470316 SCV004194642 likely pathogenic Cerebrooculofacioskeletal syndrome 2 2024-03-23 criteria provided, single submitter clinical testing

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