Submissions for variant NM_000074.3(CD40LG):c.431G>A (p.Gly144Glu)

dbSNP: rs886039326

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000255078	SCV000321507	likely pathogenic	not provided	2016-04-29	criteria provided, single submitter	clinical testing	The G144E variant has been published previously in association with X-linked hyper-IgM (Macchi et al., 1995; Prasad et al., 2005). The 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. G144E 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 in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, this variant is likely pathogenic.
Invitae	RCV002518747	SCV003445785	likely pathogenic	Hyper-IgM syndrome type 1	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 144 of the CD40LG protein (p.Gly144Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Hyper Ig M syndrome (PMID: 7717401, 15623492). ClinVar contains an entry for this variant (Variation ID: 265075). 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. This variant disrupts the p.Gly144 amino acid residue in CD40LG. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.