Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000781201 | SCV000919087 | uncertain significance | not specified | 2018-05-11 | criteria provided, single submitter | clinical testing | Variant summary: CD40LG c.429A>C (p.Lys143Asn) results in a non-conservative amino acid change located in the tumor necrosis factor domain (IPR006052) of the encoded protein sequence. In silico studies using molecular modeling predicted that the amino acid residue affected by the variant is located in the CD40L/CD40 association interface (Singh 1998). Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 199915 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.429A>C in individuals affected with Hyper IgM Syndrome Type 1 has been reported. At least one publication reports experimental evidence evaluating an impact on protein function, where site-directed mutagenesis experiments showed that the variant might affect CD40 binding (Singh 1998). However, these results do not allow convincing conclusions about the variant effect. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Invitae | RCV001314969 | SCV001505522 | uncertain significance | Hyper-IgM syndrome type 1 | 2022-02-25 | criteria provided, single submitter | clinical testing | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects CD40LG function (PMID: 9605317). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 633146). This variant has not been reported in the literature in individuals affected with CD40LG-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 143 of the CD40LG protein (p.Lys143Asn). |