Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000481348 | SCV000572927 | uncertain significance | not provided | 2017-02-09 | criteria provided, single submitter | clinical testing | The A123V variant in the CD40LG gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. However a different missense variant at this same codon (A123E) has been reported in a child with hyper-IgM syndrome (DiSanto et al., 1993). While the diagnosis of hyper-IgM was confirmed by lack of CD40LG seen in stimulated T-cells from this individual, further evidence supporting the pathogenicity of the A123E variant, such as functional studies on this specific variant, were not provided (DiSanto et al., 1993). The A123V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A123V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Based on the information available, we interpret A123V as a variant of uncertain clinical significance. |
| Invitae | RCV002526655 | SCV003487293 | uncertain significance | Hyper-IgM syndrome type 1 | 2022-08-02 | 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 expected to disrupt CD40LG protein function. ClinVar contains an entry for this variant (Variation ID: 423253). This variant has not been reported in the literature in individuals affected with CD40LG-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 123 of the CD40LG protein (p.Ala123Val). This variant disrupts the p.Ala123 amino acid residue in CD40LG. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8094231, 10559240, 15623492). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. |