Submissions for variant NM_005236.3(ERCC4):c.217A>G (p.Ile73Val)

gnomAD frequency: 0.00033  dbSNP: rs141591400

Total submissions: 7

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	2024-01-09	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 73 of the ERCC4 protein (p.Ile73Val). This variant is present in population databases (rs141591400, gnomAD 0.04%). This missense change has been observed in individual(s) with breast cancer (PMID: 24465539). ClinVar contains an entry for this variant (Variation ID: 134143). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ERCC4 protein function with a negative predictive value of 80%. 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	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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291562	SCV002584691	uncertain significance	Fanconi anemia complementation group Q	2022-10-04	criteria provided, single submitter	clinical testing	The ERCC4 c.217A>G (p.Ile73Val) missense change has a maximum subpopulation frequency of 0.037% 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.
Fulgent Genetics, Fulgent Genetics	RCV002492422	SCV002778455	uncertain significance	Xeroderma pigmentosum, group F; XFE progeroid syndrome; Fanconi anemia complementation group Q	2021-08-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002515861	SCV003661579	uncertain significance	Inborn genetic diseases	2021-07-27	criteria provided, single submitter	clinical testing	The c.217A>G (p.I73V) alteration is located in exon 2 (coding exon 2) of the ERCC4 gene. This alteration results from a A to G substitution at nucleotide position 217, causing the isoleucine (I) at amino acid position 73 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
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.