ClinVar Miner

Submissions for variant NM_001006658.2(CR2):c.2298G>A (p.Trp766Ter) (rs151093663)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000542242 SCV000652484 uncertain significance Common variable immunodeficiency 7 2020-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp766*) in the CR2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs151093663, ExAC 0.2%), including 1 homozygous individual. This variant has been observed on the opposite chromosome (in trans) from another variant (c.1225+1G>C) in an individual affected with hypogammaglobulinemia (PMID: 22035880). Family members who were heterozygous carriers of either variant were all unaffected. This finding is consistent with autosomal recessive inheritance. Experimental studies have shown that this nonsense change results in slightly reduced CR2 expression and studies performed on B cells from the affected individual demonstrate a loss of C3d-mediated co-stimulation of the B cell receptor (PMID: 22035880). Vaccination responses to protein antigens in this affected individual were normal, while the response to pneumococcal polysaccharides was moderately impaired (PMID: 22035880). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in CR2 cause disease. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000757139 SCV000885264 pathogenic not provided 2017-08-11 criteria provided, single submitter clinical testing The p.Trp766Ter variant, and c.1225+1G>C variant in compound heterozygous form, were previously reported in a 28-year old man with childhood history of recurrent respiratory tract infections, intermittent 20 years of no health concerns, and recent persistent myalgias, fevers, sore throat, chronic diarrhea as well as recurrent respiratory tract infections, splenomegaly, hypogammaglobulinemia and no expression of CD21 surface protein (Thiel 2012). Additionally, no mRNA expression was found for p.Trp766Ter and carrier mother had reduced copy number of mRNA with this variant. Furthermore, no CD21 expression was found in vitro in 293T cells with p.Trp766Ter variant (Thiel 2012). This variant is listed in the genome Aggregation Database (gnomAD) with a European (Non-Finnish) population frequency of 0.15 percent (identified on 188 out of 126,374 chromosomes including 1 homozygote). Of note, Wentink et al. (2015) described an asymptomatic 13 year old individual with hypogammaglobulinemia and two loss-of-function CR2 variants. Thus, it is conceivable that individuals with milder immunological and clinical phenotype and homozygous loss-of function CR2 variants may have their data included in gnomAD database.
GeneDx RCV000757139 SCV000890334 likely pathogenic not provided 2018-09-10 criteria provided, single submitter clinical testing The W766X variant in the CR2 gene has been reported previously in trans with a splicing variant in CR2 in a patient with hypogammaglobulinemia and recurrent infections (Thiel et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The W766X variant is observed in 188/126,374 (0.15%) alleles from individuals of non-Finnish European background, including one homozygous individual, in large population cohorts (Lek et al., 2016). We interpret W766X as a likely pathogenic variant.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000757139 SCV000891875 uncertain significance not provided 2020-09-01 criteria provided, single submitter clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000757139 SCV001447832 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000542242 SCV001192647 likely pathogenic Common variable immunodeficiency 7 2019-10-23 no assertion criteria provided clinical testing

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