ClinVar Genomic variation as it relates to human health

Converted during submission to Pathogenic.

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 35812). This premature translational stop signal has been observed in individual(s) with X-linked hyper-IgM syndrome (PMID: 9746782, 16169277, 22009004, 30405923). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg11*) in the CD40LG gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CD40LG are known to be pathogenic (PMID: 15319456).

The observed stop gained c.31C>T (p.Arg11Ter) variant in CD40LG gene has been previously reported in multiple individuals affected with hyper-IgM syndrome (Blaeser et al., 2005; Seyama et al., 1998; Kiani-Alikhan et al., 2012; Kutukculer et al., 2018). Experimental studies showed this variant to affect CD40LG function (Blaeser et al., 2005; Seyama et al., 1998; Kiani-Alikhan et al., 2012). The p.Arg11Ter variant is absent in gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic (multiple submissions). Computational evidence (MutationTaster - Disease causing) predicts damaging effect on protein structure and function for this variant. The reference amino acid of p.Arg11Ter in CD40LG is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. This sequence change creates a premature translational stop signal (p.Arg11Ter) in the CD40LG gene. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants in CD40LG gene have been previously reported to be pathogenic (Etzioni and Ochs, 2004). For these reasons, this variant has been classified as Pathogenic.