Submissions for variant NM_000074.3(CD40LG):c.478C>T (p.Gln160Ter)

dbSNP: rs767889061

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001955839	SCV002222622	pathogenic	Hyper-IgM syndrome type 1	2021-04-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the CD40LG protein. Other variant(s) that disrupt this region (p.Gln232*) have been determined to be pathogenic (PMID: 8550833, 18805740). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with hyper IgM syndrome (PMID: 24929972). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Gln160*) in the CD40LG gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 102 amino acid(s) of the CD40LG protein.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001955839	SCV002557634	pathogenic	Hyper-IgM syndrome type 1	2022-07-01	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with X-linked immunodeficiency with hyper-IgM (MIM#308230). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Variable clinical findings have been reported, even within the same family (GeneReviews). (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is NOT located at least 54 nucleotides upstream of the final exon-exon junction) with at least 1/3 of the protein sequence affected. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0600 - Variant is located in the annotated TNF (Tumour Necrosis Factor) family domain (DECIPHER). (I) 0701 – Other protein truncating variants (PTVs) comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least five PTVs that have been classified as likely pathogenic or pathogenic (ClinVar, DECIPHER). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported once in a child with X-linked immunodeficiency with hyper-IgM (PMID: 24929972). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign