ClinVar Miner

Submissions for variant NM_005236.2(ERCC4):c.217A>G (p.Ile73Val) (rs141591400)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000475162 SCV000548333 uncertain significance Xeroderma pigmentosum, group F; Cockayne syndrome; Fanconi anemia, complementation group Q 2020-07-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 73 of the ERCC4 protein (p.Ile73Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs141591400, ExAC 0.04%). This variant has been reported in an individual affected with breast cancer (PMID: 24465539). ClinVar contains an entry for this variant (Variation ID: 134143). 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 RCV001116101 SCV001274130 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.
ITMI RCV000120816 SCV000084981 not provided not specified 2013-09-19 no assertion provided reference population
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358031 SCV001553668 uncertain significance not provided no assertion criteria provided clinical testing The ERCC4 p.Ile73Val variant was identified in 1 of 126 proband chromosomes (frequency: 0.0079) from individuals or families with breast cancer (Kohlhase_2014_PMID: 24465539). The variant was identified in dbSNP (ID: rs141591400) and ClinVar, where it was classified as a VUS by Invitae and was unclassified by ITMI (Inova Translational Medicine Institute). The variant was also found in LOVD 3.0 but not in Cosmic. The variant was identified in control databases in 62 of 282586 chromosomes at a frequency of 0.000219 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 48 of 129020 chromosomes (freq: 0.000372), Latino in 10 of 35398 chromosomes (freq: 0.000283), other in 1 of 7218 chromosomes (freq: 0.000139), African in 2 of 24954 chromosomes (freq: 0.00008) and South Asian in 1 of 30582 chromosomes (freq: 0.000033); it was not observed in the Ashkenazi Jewish and East Asian populations. 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. The p.Ile73 residue is conserved in mammals but not in more distantly related organisms and four of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein;this information is not predictive enough to rule out pathogenicity. 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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