Submissions for variant NM_005236.3(ERCC4):c.2480C>A (p.Thr827Lys)

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002292233	SCV002584657	uncertain significance	Fanconi anemia complementation group Q	2022-09-22	criteria provided, single submitter	clinical testing	The ERCC4 c.2480C>A (p.Thr827Lys) missense change has a maximum subpopulation frequency of 0.00088% 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003101682	SCV003021382	uncertain significance	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2022-03-14	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with ERCC4-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 827 of the ERCC4 protein (p.Thr827Lys).