ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.2169C>A (p.Cys723Ter)

gnomAD frequency: 0.00001  dbSNP: rs2020959
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000822020 SCV000962800 pathogenic Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q 2023-06-21 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Cys723*) in the ERCC4 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 194 amino acid(s) of the ERCC4 protein. This variant is present in population databases (rs2020959, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with giant cell tumor of the bone and in an individual with alveolar rhabdomyosarcoma (PMID: 28878254). ClinVar contains an entry for this variant (Variation ID: 664022). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ERCC4 function (PMID: 24412486). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Arg799 amino acid residue in ERCC4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8797827, 9579555, 20221251, 23623389, 26074087, 29403087, 29892709). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
GeneDx RCV001194781 SCV005079693 likely pathogenic not provided 2024-06-08 criteria provided, single submitter clinical testing Identified in the heterozygous state in patients with sarcoma, breast cancer, and colon cancer in the published literature, however, familial segregation data was not included (PMID: 28878254, 31350202); Published functional studies suggest a damaging effect (PMID: 24412486); Nonsense variant predicted to result in protein truncation, as the last 194 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD or GeneDx.; This variant is associated with the following publications: (PMID: 24412486, 28878254, 35929646, 31350202)
Fulgent Genetics, Fulgent Genetics RCV005021255 SCV005645269 likely pathogenic Xeroderma pigmentosum, group F; XFE progeroid syndrome; Fanconi anemia complementation group Q 2024-02-08 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV001194781 SCV001364567 uncertain significance not provided 2017-03-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Gerard C.P. Schaafsma.

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