Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000803202 | SCV000943064 | pathogenic | Hyper-IgM syndrome type 1 | 2022-06-20 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 648466). This missense change has been observed in individual(s) with clinical features of X-linked hyper-immunoglobulin M (IgM) syndrome (PMID: 22963373; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 125 of the CD40LG protein (p.His125Tyr). 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. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.His125 amino acid residue in CD40LG. Other variant(s) that disrupt this residue have been observed in individuals with CD40LG-related conditions (PMID: 8889581), which suggests that this may be a clinically significant amino acid residue. |
| Lifecell International Pvt. |
RCV000803202 | SCV003852647 | likely pathogenic | Hyper-IgM syndrome type 1 | criteria provided, single submitter | clinical testing | A Hemizygote Missense variant c.373C>T in Exon 4 of the CD40LG gene that results in the amino acid substitution p.His125Tyr was identified. The observed variant is novel ingnomAD exomes and genomes. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score. Rare Exome Variant EnsembleLearner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Likely Pathogenic [Variation ID: 648466]. The variant has been previously reported in patients affected with Immunodeficiency with hyper IgM (Du, Xiao et al.,2019). For these reasons, this variant has been classified as Likely Pathogenic. |