Submissions for variant NM_021922.3(FANCE):c.1378C>T (p.Arg460Trp)

dbSNP: rs200535245

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000376250	SCV000462673	uncertain significance	Fanconi anemia complementation group E	2018-01-12	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000376250	SCV002303687	uncertain significance	Fanconi anemia complementation group E	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 460 of the FANCE protein (p.Arg460Trp). This variant is present in population databases (rs200535245, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with FANCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 356452). 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 expected to disrupt FANCE protein function. 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.
Fulgent Genetics, Fulgent Genetics	RCV000376250	SCV002778681	uncertain significance	Fanconi anemia complementation group E	2022-05-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV003151044	SCV003839518	uncertain significance	not specified	2022-12-19	no assertion criteria provided	clinical testing	DNA sequence analysis of the FANCE gene demonstrated a sequence change, c.1378C>T, in exon 8 that results in an amino acid change, p.Arg460Trp. This sequence change does not appear to have been previously described in individuals with FANCE-related disorders. This sequence change has been described in the gnomAD database with a frequency of 0.01 in the South Asian subpopulation (dbSNP rs200535245). The p.Arg460Trp change affects a moderately conserved amino acid residue located in a domain of the FANCE protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Arg460Trp substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg460Trp change remains unknown at this time.