ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.1268A>G (p.Tyr423Cys)

gnomAD frequency: 0.00011  dbSNP: rs143924094
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001967608 SCV002209932 uncertain significance Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q 2022-10-01 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERCC4 protein function. ClinVar contains an entry for this variant (Variation ID: 1431747). This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. This variant is present in population databases (rs143924094, gnomAD 0.04%). This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 423 of the ERCC4 protein (p.Tyr423Cys).
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003230289 SCV003928086 uncertain significance Xeroderma pigmentosum, group F 2023-03-31 criteria provided, single submitter clinical testing The ERCC4 c.1268A>G (p.Tyr423Cys) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. To our knowledge, this variant has not been reported in individuals with Fanconi anemia or Xeroderma pigmentosum. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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