ClinVar Miner

Submissions for variant NM_000400.3(ERCC2):c.2164C>T (p.Arg722Trp) (rs121913026)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255624 SCV000322047 pathogenic not provided 2018-12-12 criteria provided, single submitter clinical testing The R722W pathogenic variant in the ERCC2 gene has been reported previously in the homozygous state or in trans with another ERCC2 variant in multiple individuals with trichothiodystrophy (Takayama et al., 1996; Usuda et al., 2011; Pehlivan et al., 2012). It is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The R722W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In vitro functional studies show that the R722W variant disrupts RARB2 mRNA synthesis by deregulating several transcriptional steps and destabilizes the architecture of the evolutionarily conserved general transcription factor IIH (TFIIH) (Singh et al., 2015). We interpret R722W as a pathogenic variant.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV000677676 SCV000803818 pathogenic Cerebrooculofacioskeletal syndrome 2 2014-01-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763052 SCV000893533 pathogenic Cerebrooculofacioskeletal syndrome 2; Xeroderma pigmentosum, group D; Trichothiodystrophy 1, photosensitive 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000255624 SCV001248922 pathogenic not provided 2018-07-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001199920 SCV001370695 pathogenic Trichothiodystrophy 2020-05-28 criteria provided, single submitter clinical testing Variant summary: ERCC2 c.2164C>T (p.Arg722Trp) 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 2.4e-05 in 251074 control chromosomes. c.2164C>T has been reported in the literature in individuals affected with Trichothiodystrophy (e.g. Takayama_1996, Taylor_1997, Usuda_2011, Zhou_2013). 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 and showed that p.Arg722Trp affected normal activity (e.g. Singh_2015). 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. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000018283 SCV000038562 pathogenic Trichothiodystrophy 1, photosensitive 1994-06-01 no assertion criteria provided literature only

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