ClinVar Miner

Submissions for variant NM_000074.2(CD40LG):c.655G>A (p.Gly219Arg) (rs148594123)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000358482 SCV000336027 benign not specified 2016-07-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000029465 SCV000602939 likely benign Hyper-IgM syndrome type 1 2019-09-19 criteria provided, single submitter clinical testing
Invitae RCV000029465 SCV000634149 benign Hyper-IgM syndrome type 1 2020-12-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000358482 SCV000695311 benign not specified 2016-04-08 criteria provided, single submitter clinical testing Variant summary: The CD40LG c.655G>A variant affects a non-conserved nucleotide, resulting in amino acid change from Gly to Arg. 3/5 in-silico tools predict this variant to be damaging. In vitro functional studies suggest that G219R has decreased ligand binding and decreased capacity to activate B cells. However, the single expression of G219R protein has no or only minor effects in vivo as shown by an asymptomatic carrier of G219R who has normal values of serum IgA and IgM and normal B-cell subpopulations (Rigaud 2011). These functional studies suggest that this variant is a functional polymorphism.This variant was found in 992/88003 control chromosomes (at least 7 homozygotes and 388 hemizygotes) at a frequency of 0.0112723, which is about 7 times the maximal expected frequency of a pathogenic CD40LG allele (0.0015811) for HIGM1, suggesting this variant is benign. The variant has been reported in patients with hyper IgM syndrome, non-X-linked HIGM, X-linked variable immunodeficiency, and hypogammaglobulinemia, However, some of these patients had other probable disease causing mutations in cis (Gln232X; Lin 1996) or in another gene (XIAP G466X; Rigaud 2011), or unaffected compound heterozygous or hemizygous family members (lack of segregation with disease; Martinez-Martinez 2012 and Rigaud 2011), suggesting that this variant itself is not pathogenic in isolation. Taken together, this variant is not disease causing in isolation but may play a contributory role in certain backgrounds, and therefore is classified as benign.

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