ClinVar Miner

Submissions for variant NM_000074.2(CD40LG):c.761C>T (p.Thr254Met) (rs193922136)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000029466 SCV000052116 pathogenic X-linked hyper-IgM syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000588005 SCV000695312 pathogenic Hyperimmunoglobulin M syndrome 2016-02-26 criteria provided, single submitter clinical testing Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and polar Threonine (T) with a medium size and hydrophobic Methionine (M) affecting the internal core packaging of the CD40L monomer (Seyama_Blood_1998). 5/5 in silico tools predict the variant to be disease causing. The variant is absent for the large and broad cohorts of the ExAC project while it was reported in several Hyper IgM Syndrome patients indicating pathogenicity. Patients with the variant of interest show abolished CD40-Ig expression (Seyama_Blood_1998; Cabral-Marques_JCI_2014) further supporting pathogenicity. Moreover, reputable databases classify variant as pathogenic. Considering all evidence, the variant was classified as a Pathogenic.
Invitae RCV000029466 SCV000939437 pathogenic X-linked hyper-IgM syndrome 2019-11-03 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 254 of the CD40LG protein (p.Thr254Met). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with X-linked hyper IgM syndrome in several families (PMID: 10484640). It has also been reported in several individuals with a milder phenotype (PMID: 25541662, 10484640, 19575287, 17351759). This variant is also known as 782C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 35814). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). For these reasons, this variant has been classified as Pathogenic.
GeneReviews RCV000029466 SCV001364082 pathogenic X-linked hyper-IgM syndrome 2020-02-13 no assertion criteria provided literature only

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