ClinVar Miner

Submissions for variant NM_000400.4(ERCC2):c.2164C>T (p.Arg722Trp) (rs121913026)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255624 SCV000322047 pathogenic not provided 2021-12-06 criteria provided, single submitter clinical testing Published functional studies demonstrate that R722W 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); 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: 18817897, 25431422, 7920640, 15494306, 26577220, 23232694, 23221806, 23039039, 20944642, 25620205, 22705887, 12820975, 27862069, 8571952, 28724667, 19085937, 31282071, 31589614, 32732226, 31980526, 31803976)
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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego RCV001265586 SCV001443751 pathogenic ERCC2-related conditions 2019-11-20 criteria provided, single submitter clinical testing This variant has been previously reported as a compound heterozygous and homozygous change in patients with trichothiodystrophy (PMID: 8571952, 19085937, 20944642, 23232694, 26577220). Functional studies using patient fibroblast cell lines show that this variant impedes the recruitment of transcription repair factor TFIIH to sites of DNA damage, at least in part by weakening the interaction of ERCC2 with the GTF2H2 subunit (PMID: 18817897, 25620205). Another study using patient fibroblast cells shows that this variant results in a drastic reduction in the expression of collagen type VI alpha1 subunit, an important component of soft connective tissues, due to impaired TFIIH function (PMID: 23221806). This variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.003% (9/276898) and thus is presumed to be rare. The c.2164C>T (p.Arg722Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.2164C>T (p.Arg722Trp) variant is classified as Pathogenic.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV001449816 SCV001653116 pathogenic Hypotrichosis simplex 2021-03-05 criteria provided, single submitter clinical testing The p.Arg722Trp variant in ERCC2 has been reported in >10 individuals with trichothiodystrophy (TTD) as homozygous or in trans with a second pathogenic ERCC2 variant (Takayama 1996 PMID:8571952, Stefanini 2010 PMID:19931493, Pehlivan 2012 PMID:23039039). It has also been identified in 0.005% (6/128882) of European chromosomes by gnomAD (; however, this frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID 16792). In vitro functional studies support an impact on protein function (Pehlivan 2012 PMID:23039039, Singh 2015 PMID:25620205). Mouse models have shown that this variant causes TTD (deBoer 1998 PMID: 9651581). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive TTD. ACMG/AMP Criteria applied: PS3, PM3_Strong, PM2_Supporting.
OMIM RCV000018283 SCV000038562 pathogenic Trichothiodystrophy 1, photosensitive 1994-06-01 no assertion criteria provided literature only
Service de Génétique Moléculaire,Hôpital Robert Debré RCV000677676 SCV001432347 pathogenic Cerebrooculofacioskeletal syndrome 2 no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000255624 SCV001808663 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000255624 SCV001951010 pathogenic not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000255624 SCV001973214 pathogenic not provided no assertion criteria provided clinical testing

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