ClinVar Miner

Submissions for variant NM_005236.3(ERCC4):c.2117T>C (p.Ile706Thr)

gnomAD frequency: 0.00096  dbSNP: rs1800069
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463526 SCV000548331 benign Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia complementation group Q 2021-12-16 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000120815 SCV000594575 uncertain significance not specified 2016-12-05 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV001121237 SCV001279806 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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics RCV001332584 SCV001524956 uncertain significance XFE progeroid syndrome 2019-05-09 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001121237 SCV002009702 uncertain significance Xeroderma pigmentosum, group F 2021-11-03 criteria provided, single submitter clinical testing
Baylor Genetics RCV001788036 SCV002030259 uncertain significance Fanconi anemia complementation group Q 2021-03-03 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001788036 SCV002032318 uncertain significance Fanconi anemia complementation group Q 2022-09-09 criteria provided, single submitter clinical testing The ERCC4 c.2117T>C (p.Ile706Thr) missense change has a maximum subpopulation frequency of 0.24% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with ataxia (PMID: 31692161), head and neck squamous cell carcinoma (PMID: 28678401), and pancreatic ductal adenocarcinoma (PMID: 28767289). 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.
Sema4,Sema4 RCV002257430 SCV002537939 likely benign Xeroderma pigmentosum 2020-11-29 criteria provided, single submitter curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120815 SCV002548370 benign not specified 2022-05-26 criteria provided, single submitter clinical testing Variant summary: ERCC4 c.2117T>C (p.Ile706Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251444 control chromosomes (gnomAD), predominantly at a frequency of 0.0025 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in ERCC4 causing Xeroderma Pigmentosum phenotype (0.00019), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance and one as benign. Based on the evidence outlined above, the variant was classified as benign.
ITMI RCV000120815 SCV000084980 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354835 SCV001549546 uncertain significance not provided no assertion criteria provided clinical testing The ERCC4 p.Ile706Thr variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs1800069), LOVD 3.0 and ClinVar (classified as uncertain significance by Genetic Services Laboratory, University of Chicage, and as likely benign by Invitae). The variant was identified in control databases in 366 of 268308 chromosomes (1 homozygous) at a frequency of 0.001364 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: European (non-Finnish) in 283 of 118142 chromosomes (freq: 0.002395), Other in 12 of 6702 chromosomes (freq: 0.001791), Latino in 50 of 35108 chromosomes (freq: 0.001424), European (Finnish) in 11 of 25108 chromosomes (freq: 0.000438), African in 9 of 23614 chromosomes (freq: 0.000381) and Ashkenazi Jewish in 1 of 9858 chromosomes (freq: 0.000101), but was not observed in the East Asian or South Asian populations. The p.Ile706 residue is conserved in mammals but not in more distantly related organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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. 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.

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