ClinVar Genomic variation as it relates to human health

Variant summary: The variant identified by MLPA or other technology involves the duplication of exons 1-14, i.e. the whole coding sequence of the FAN1 (aka. MTMR15) gene. Since the exact breakpoints of this duplication are not known, it might extend beyond the assayed region of the gene, and include other flanking genes. A presumed nomenclature of c.(?_-292)_(*3+1_*4-1)dup has been designated for the purposes of this classification. It has been assumed that this is a tandem duplication in direct orientation (Richardson_GIM_2018, Newman_AJHG_2015). A large duplication variant (~323 kbp) involving the FAN1 gene (together with the full- and partial duplications of other flanking genes) was found at a frequency of 0.0001383 (i.e. 3 heterozygous alleles) in 21694 control chromosomes in the gnomAD database, structural variants dataset. To our knowledge, no occurrence of c.(?_-292)_(*3+1_*4-1)dup in individuals affected with Karyomegalic Interstitial Nephritis and no experimental evidence demonstrating its impact on protein function have been reported. On the other hand, large duplication variants involving the FAN1 gene, together with other genes, have been reported in individuals affected with various phenotypes (USCS), however without presenting evidence for causality of the FAN1 gene. ClinVar lists several large duplication variants spanning multiple genes (including FAN1) as pathogenic or VUS, but provides no phenotype or classification details. Based on the evidence outlined above, the variant was classified as uncertain significance.