ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.1762G>A (p.Val588Ile)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002963014 SCV003289139 uncertain significance Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q 2023-12-07 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 588 of the ERCC4 protein (p.Val588Ile). This variant is present in population databases (rs777006157, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. ClinVar contains an entry for this variant (Variation ID: 2074753). 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 with a negative predictive value of 80%. 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.
Revvity Omics, Revvity RCV003146704 SCV003833580 uncertain significance not provided 2023-01-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV003170767 SCV003867343 uncertain significance Inborn genetic diseases 2023-02-16 criteria provided, single submitter clinical testing The c.1762G>A (p.V588I) alteration is located in exon 8 (coding exon 8) of the ERCC4 gene. This alteration results from a G to A substitution at nucleotide position 1762, causing the valine (V) at amino acid position 588 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003325242 SCV004031109 uncertain significance Fanconi anemia complementation group Q 2023-08-01 criteria provided, single submitter clinical testing The ERCC4 c.1762G>A (p.Val588Ile) missense change has a maximum subpopulation frequency of 0.005% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a benign effect on protein function, but this prediction has not been confirmed by functional studies. 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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