Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000480912 | SCV000571450 | likely pathogenic | not provided | 2016-08-22 | criteria provided, single submitter | clinical testing | The M36K variant in the CD40LG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although this substitution occurs at a position where amino acids with similar properties to Methionine are tolerated across species, the M36K 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. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A missense variant in the same residue (M36R) has been reported in association with hyper-IgM syndrome (Korthauer et al., 1993), supporting the functional importance of this region of the protein. The M36K variant is a strong candidate for a pathogenic variant, however the possibility it my be a rare benign variant cannot be excluded. |
| Invitae | RCV001368065 | SCV001564441 | uncertain significance | Hyper-IgM syndrome type 1 | 2020-10-12 | criteria provided, single submitter | clinical testing | Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CD40LG protein function. 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. This variant disrupts the p.Met36 amino acid residue in CD40LG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7679206, 15358621). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This variant has not been reported in the literature in individuals with CD40LG-related conditions. ClinVar contains an entry for this variant (Variation ID: 422070). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with lysine at codon 36 of the CD40LG protein (p.Met36Lys). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and lysine. |
| OMIM | RCV001368065 | SCV002546230 | pathogenic | Hyper-IgM syndrome type 1 | 2022-07-13 | no assertion criteria provided | literature only |