ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.1765C>T (p.Arg589Trp)

dbSNP: rs147105770
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory,University of Chicago RCV000049250 SCV000594580 likely pathogenic Xeroderma pigmentosum, type F/Cockayne syndrome 2017-01-19 criteria provided, single submitter clinical testing
Invitae RCV000700109 SCV000828850 pathogenic Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q 2021-08-28 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762956 SCV000893393 pathogenic Xeroderma pigmentosum, group F; XFE progeroid syndrome; Fanconi anemia complementation group Q 2018-10-31 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222373 SCV002500097 pathogenic Xeroderma pigmentosum 2022-03-04 criteria provided, single submitter clinical testing Variant summary: ERCC4 c.1765C>T (p.Arg589Trp) 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 6.4e-05 in 249106 control chromosomes (gnomAD). This frequency is not higher than the estimated maximum expected for a pathogenic variant in ERCC4 causing Xeroderma Pigmentosum (6.4e-05 vs 0.00019), allowing no conclusion about variant significance. The variant, c.1765C>T, has been reported in the literature in multiple individuals affected with Xeroderma Pigmentosum (e.g. Ahmad_2010, Gregg_2011, Manandhar_2015, Fassihi_2016, Shanbhag_2018) and some affected individuals also had Fanconi anemia, although with varying severity (e.g. Kashiyama_2013, Popp_2018). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated disrupted protein-protein interaction with SLX4 (Hashimoto_2015), mislocalization to the cytoplasm and strong hypersensitivity to UV and cross-linking agents in cells transfected with the variant protein (Sabatella_2018). 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 (n=1) / likely pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000049250 SCV000077503 pathogenic Xeroderma pigmentosum, type F/Cockayne syndrome 2013-05-02 no assertion criteria provided literature only

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