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
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755229 SCV000602939 likely benign not provided 2017-07-14 criteria provided, single submitter clinical testing The c.655G>A; p.Gly219Arg variant (rs148594123; ClinVar ID: 35813) is listed in the genome Aggregation Database (gnomAD) with a non-Finnish European allele frequency of 1.6% (identified in 1,437 out of 90,078 chromosomes, including 7 homozygotes and 505 hemizygotes). The glycine at position 219 is moderately conserved, considering 11 species, and computational analyses of the effects of the p.Gly219Arg variant on protein structure and function do not predict a deleterious effect (SIFT; tolerated, PolyPhen-2: benign). In vitro studies have shown that the p.Gly219Arg variant protein has weaker capacity to bind to a CD40 recombinant fusion protein compared with wild type, and has decreased capacity to activate B cells (Rigaud 2011). The authors proposed that Gly219Arg acts as a second genetic factor, together with a p.Gly466Ter variant (reported as G466X) identified in the XIAP gene, in patients with hypogammaglobulinemia. The p.Gly219Arg variant has also been reported in a 15 year old individual who was diagnosed with hyper Ig-M syndrome, with chronic cough, pneumonia, fatigue, nasal congestion, recurrent sinusitis, otitis media, severe varicella as an infant, herpes zoster at age 10, chronic gingivitis, aplastic anemia at age 5, Crohn's disease at age 8, and weight loss, and who had decreased CD40L expression and CD40-Ig binding (Katta 2013). However, this variant has also been seen in healthy individuals, including a mother with complete deletion of the CD40LG allele in trans who had normal lymphocyte counts and immunoglobulin levels (Martinez-Martinez 2012), and an individual who has been asymptomatic, with normal IgA and IgM values and normal B cell subpopulations, since an episode of hypogammaglobulinemia and recurrent infections at 6 months (Rigaud 2011). The p.Gly219Arg variant was also reported in 1.2% of controls in another study, prompting the conclusion that it seems to be disease-contributing rather than disease-causing (Aghamohammadi 2009). Based on the available information, the p.Gly219Arg variant is likely to be benign. Even if this variant is later determined to be disease-contributing together with pathogenic variants in XIAP, please note that this test includes XIAP gene analysis and no pathogenic variants, including p.Gly466Ter, were detected in the XIAP gene.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000358482 SCV000336027 benign not specified 2016-07-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.
Invitae RCV000029465 SCV000634149 benign Immunodeficiency with hyper IgM type 1 2017-08-17 criteria provided, single submitter clinical testing

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