ClinVar Miner

Submissions for variant NM_005236.2(ERCC4):c.1727G>C (p.Arg576Thr) (rs1800068)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000651477 SCV000773329 uncertain significance Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia, complementation group Q 2020-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with threonine at codon 576 of the ERCC4 protein (p.Arg576Thr). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and threonine. This variant is present in population databases (rs1800068, ExAC 0.1%). This variant has been observed in several individuals affected with head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma (PMID: 28678401, 28767289). ClinVar contains an entry for this variant (Variation ID: 134158). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 Clinical Services Laboratory,Illumina RCV001119237 SCV001277596 uncertain significance Xeroderma pigmentosum, group F 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV001294105 SCV001482918 uncertain significance Fanconi anemia, complementation group Q 2019-09-26 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
ITMI RCV000120831 SCV000084996 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357601 SCV001553115 uncertain significance not provided no assertion criteria provided clinical testing The ERCC4 p.Arg576Thr variant was identified in 10 of 6374 proband chromosomes (frequency: 0.001569) from individuals with breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma or head and neck squamous cell carcinoma and was present in 2 of 154 control chromosomes (frequency: 0.01299) from healthy individuals (McVeigh_2020_PMID:32008151; West_2018; Shindo_2017_PMID:28767289; Chandrasekharappa_2017_PMID:28678401). The variant was identified in dbSNP (ID: rs1800068) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 185 of 281516 chromosomes at a frequency of 0.0006572 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 45 of 35426 chromosomes (freq: 0.00127), European (non-Finnish) in 126 of 127888 chromosomes (freq: 0.000985), Other in 7 of 7216 chromosomes (freq: 0.00097), African in 5 of 24972 chromosomes (freq: 0.0002) and European (Finnish) in 2 of 25102 chromosomes (freq: 0.00008), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Arg576 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional assays demonstrated defective DNA repair function after UV-induced DNA damage with ERCC4 p.R576T compared to wildtype (West_2018). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV001357601 SCV001742068 uncertain significance not provided no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.