ClinVar Miner

Submissions for variant NM_000400.3(ERCC2):c.2047C>T (p.Arg683Trp) (rs41556519)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000623275 SCV000742609 likely pathogenic Inborn genetic diseases 2017-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: UNCERTAIN: Alteration(s) of Uncertain Clinical Significance Detected
Fulgent Genetics RCV000763053 SCV000893534 pathogenic Cerebrooculofacioskeletal syndrome 2; Xeroderma pigmentosum, group D; Trichothiodystrophy 1, photosensitive 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000518900 SCV000617488 pathogenic not provided 2017-05-09 criteria provided, single submitter clinical testing The R683W variant in the ERCC2 gene has been reported previously in the homozygous and compound heterozygous state in multiple unrelated individuals with xeroderma pigmentosa (Takayama et al., 1995; Lai et al., 2013; Taylor et al., 1997). The R683W variant is observed in 1/10370 (0.01%) alleles from individuals of African background in the ExAC dataset, and no individuals were reported to be homozygous (Lek et al., 2016). The R683W 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. This substitution occurs at a position that is conserved across species. Functional studies of R683W cells showed the recruitment of TFIIH and NER factors were highly deregulated at early time points, weakening the interaction with GTF2H2 subunit and destabilizing the architecture of TFIIH (Singh et al., 2015). A missense variant in the same residues (R683W) has been reported in association with ERCC2-related disorders in multiple unrelated individuals, supporting the functional importance of this region of the protein (Nakano et al., 2014; Schafer et al., 2013; Falik-Zaccai et al., 2012; Taylor et al., 1997). We interpret R683W as a pathogenic variant.
GeneReviews RCV000018284 SCV000320712 pathogenic Xeroderma pigmentosum, group D 2016-09-26 no assertion criteria provided literature only
OMIM RCV000018284 SCV000038563 pathogenic Xeroderma pigmentosum, group D 2004-10-22 no assertion criteria provided literature only

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