ClinVar Genomic variation as it relates to human health

This CNV is a 106 kb loss of chromosome 1 at 1q23.3, (seq[GRCh37]del(1)(1q23.3; chr1:g.161279433_161385237del), of unknown inheritance. This CNV affects three protein coding genes, including CFAP126, SDHC, and MPZ. It constitutes a full deletion of the SDHC gene and a deletion of exon 1 of the MPZ gene. SDHC haploinsufficiency is a well-established mechanism for hereditary paraganglioma-pheochromocytoma syndrome, with single and multi-exon deletions as well as essential splice and stop-gained variants reported (Else et al. 2008). Loss of function or disruption of the MPZ gene, including due to copy number variants, is a known cause of Charcot-Marie-Tooth disease and other MPZ-related disorders (DiVincenzo et al. 2014; Salpietro et al. 2018). Loss of exon 1, including the initiation codon, is predicted to severely disrupt protein expression, as there is no nearby alternative start site. The functional consequences of this deletion on MPZ function have not been evaluated experimentally, but a variant disrupting the initiation codon has been previously reported in an affected individual (DiVincenzo et al. 2014). Similar deletions have not been reported in controls. Based on this evidence, this CNV is classified as pathogenic.