Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000423996 | SCV000521152 | likely pathogenic | not provided | 2016-10-11 | criteria provided, single submitter | clinical testing | The F256S variant in the CD40LG gene has been reported previously in association with hyper IgM syndrome (Wang et al., 2014; Kojima et al., 2016). The F256S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The F256S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (G252D, F253I, T254M, G257S, G257D, G257V, L258S) have been reported in the Human Gene Mutation Database in association with hyper IgM syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. The F256S variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. |
| Invitae | RCV001378166 | SCV001575677 | likely pathogenic | Hyper-IgM syndrome type 1 | 2020-05-15 | criteria provided, single submitter | clinical testing | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with hyper-IgM syndrome (PMID: 25215306, 26997321, Invitae). ClinVar contains an entry for this variant (Variation ID: 381653). This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with serine at codon 256 of the CD40LG protein (p.Phe256Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. |