ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.1763T>C (p.Val588Ala)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV002976548 SCV003290044 uncertain significance Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 588 of the ERCC4 protein (p.Val588Ala). This variant is present in population databases (rs371392134, gnomAD 0.05%). 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: 2077533). 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 expected to disrupt ERCC4 protein function with a positive 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.
Ambry Genetics RCV002976549 SCV003737502 uncertain significance Inborn genetic diseases 2021-10-27 criteria provided, single submitter clinical testing The c.1763T>C (p.V588A) alteration is located in exon 8 (coding exon 8) of the ERCC4 gene. This alteration results from a T to C substitution at nucleotide position 1763, causing the valine (V) at amino acid position 588 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003325243 SCV004031202 uncertain significance Fanconi anemia complementation group Q 2023-05-23 criteria provided, single submitter clinical testing The ERCC4 c.1763T>C (p.Val588Ala) missense change has a maximum subpopulation frequency of 0.048% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious 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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