Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000636648 | SCV000758087 | likely pathogenic | Hyper-IgM syndrome type 1 | 2018-10-31 | 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. A different missense substitution at this codon (p.Thr254Met) has been determined to be pathogenic (PMID: 8889581, 10484640, 25541662). This suggests that the threonine residue is critical for CD40LG protein function and that other missense substitutions at this position may also be pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has has been reported to segregate with hyper IgM syndrome in a single family (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with lysine at codon 254 of the CD40LG protein (p.Thr254Lys). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and lysine. |