Submissions for variant NM_005236.3(ERCC4):c.532G>T (p.Val178Leu)

gnomAD frequency: 0.00070  dbSNP: rs149927607

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000536696	SCV000654065	uncertain significance	Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q	2022-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 178 of the ERCC4 protein (p.Val178Leu). This variant is present in population databases (rs149927607, gnomAD 0.06%). This missense change has been observed in individual(s) with pancreatic ductal adenocarcinoma (PMID: 28767289). ClinVar contains an entry for this variant (Variation ID: 474207). 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. 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.
Illumina Laboratory Services, Illumina	RCV001121126	SCV001279678	uncertain significance	Xeroderma pigmentosum, group F	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001764609	SCV002008777	uncertain significance	not provided	2020-04-24	criteria provided, single submitter	clinical testing	Identified in an individual with pancreatic ductal adenocarcinoma; considered a variant of uncertain significance by the authors (Shindo et al., 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28767289)
Genetic Services Laboratory, University of Chicago	RCV001821618	SCV002071253	uncertain significance	not specified	2021-07-13	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ERCC4 gene demonstrated a sequence change, c.532G>T, in exon 3 that results in an amino acid change, p.Val178Leu. This sequence change has been described in the gnomAD database with frequency of 0.059% in the non-Finnish European subpopulation (dbSNP rs149927607). The p.Val178Leu change affects a moderately conserved amino acid residue located in a domain of the ERCC4 protein that is known to be functional. The p.Val178Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been reported in an individual with pancreatic adenocarcinoma and a family history of lymphoma and brain cancer (PMID: 28767289). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val178Leu change remains unknown at this time.