ClinVar Miner

Submissions for variant NM_012452.2(TNFRSF13B):c.310T>C (p.Cys104Arg) (rs34557412)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507544 SCV000605391 pathogenic not specified 2016-06-23 criteria provided, single submitter clinical testing
Blueprint Genetics, RCV000403933 SCV000927312 uncertain significance not provided 2017-06-26 criteria provided, single submitter clinical testing
CHLA Center for Personalized Medicine,Children's Hospital, Los Angeles RCV000735370 SCV000854523 uncertain significance Talipes equinovarus; Skeletal dysplasia; Micrognathia; Hemivertebrae; Preaxial foot polydactyly; Respiratory failure; Short femur; Vertebral segmentation defect; Pseudoarthrosis; Chronic lung disease; Interstitial pulmonary abnormality; Coat hanger sign of ribs; Vertebral hypoplasia; Absent epiphyses; Cleft palate; Patent ductus arteriosus criteria provided, single submitter clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000403933 SCV000610665 likely benign not provided 2017-09-25 criteria provided, single submitter clinical testing
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000005623 SCV000590895 risk factor Common variable immunodeficiency 2 2017-06-07 criteria provided, single submitter clinical testing
GeneDx RCV000403933 SCV000329550 pathogenic not provided 2018-10-02 criteria provided, single submitter clinical testing The C104R variant in the TNFRSF13B gene has been reported previously in association with both autosomal dominant and autosomal recessive forms of CVID and immunoglobulin A deficiency; however, this variant is most commonly associated with autosomal recessive inheritance (Salzer et al., 2009; Barroeta Seijas et al., 2012; Speletas et al., 2013; Martinez-Gallo et al., 2013; Lucena et al., 2015). Although an individual who was homozygous for the C104R variant has been reported to be clinically unaffected, his homozygous siblings had decreased immunoglobulin levels and were symptomatic (Martinez-Gallo et al., 2013). Functional studies have shown that the C104R variant is associated with impaired ligand binding and impaired B-cell function (Lee at al., 2010; Fried et al., 2011). Additionally, defective intracellular and extracellular expression of the gene is observed in individuals with CVID who are homozygous for the C104R variant, as well as in their clinically unaffected heterozygous relatives (Martinez-Gallo et al, 2013). The C104R variant is observed in 960/277246 (0.35%) alleles in large population cohorts, including 4 homozygotes (Lek et al., 2016). The C104R variant is a non-conservative amino acid substitution, which occurs at a position within the cysteine-rich domain 2, a region involved in disulfide bond formation (Hymowitz et al., 2005). We interpret C104R as a pathogenic variant.
Illumina Clinical Services Laboratory,Illumina RCV000302082 SCV000400917 likely benign Common Variable Immune Deficiency, Dominant 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000403933 SCV000699342 uncertain significance not provided 2016-04-13 criteria provided, single submitter clinical testing Variant summary: The composite allele frequency of this variant is 1/309 in the general population. [Considering a recessive mode of inheritance, the maximal expected allele frequency of a disease-causing TNFRS13B allele is 1/418 (0.24%).] (Since there are other reported pathogenic TNFRS13B variants (e.g: pSer144X, p.Ser194Ter) that contribute to the disease, the observed allele frequency of 1/309 for the variant suggests that it is in the benign spectrum or is a low penetrance allele.) In families reported to carry this variant, there is no clear-cut inheritance pattern for it; however, recessive inheritance is supported by several studies. The dominant mode of inheritance is ruled out by high prevalence of the variant in controls as well as lack of cosegregation of this variant in dominant form in multiple reports (such as Poodt et al 2009). There are several reports that find the variant in compound heterozygousity as well as in homozygosity with CVID phenotype. In all compound heterozygous pts, second mutations inheritance (whether dominant or recessive mutation) can not been ascertained. However, there are also reports that subjects with this homozygous variant do not have CVID (Martnez-Pomar et al 2009) or do not fulfill diagnostic criteria for CVID (Koopmans et al 2013). These findings may suggest that this variant might be a recessive reduced penetrance mutation; however, the data are not clear enough. The functional data are suggestive of impaired activity of the variant; however, in lack of definitive genotype and phenotype data to support for pathogenicity, we cannot let functional data alone drive the variants pathogenicity. Martinez-Gallo et al 2013 showed that family members with the mutation in heterozygous or homozygous form, although not hypogammaglobulinemic, still have impaired B-cell TACI expression, reduced ligand binding, and markedly defective upregulation of AID mRNA, showing a dominantly inherited, selective in vitro activation defect. The authors conclude that, B cells of relatives of subjects with CVID who have mutations in TACI but normal immune globulin levels still have detectable in vitro B-cell defects. Moreover, Romberg et al 2013 also conclude that this mutation may favor CVID by altering B cell activation with coincident impairment of central B cell tolerance.Some case-control studies show that this variant might be associated with increased disease risk; however, odds ratios are not high to derive a definitive conclusion. Freiberger et al 2012 concludes, The p.C104R and p.A181E mutations and premature stop codon introducing mutations appear to be relevant, either alone or more likely in combination with other genetic and/or environmental factor(s), although statistically significant association was only demonstrated with CVID for the p.C104R, p.A181E and p.L69TfsX12 mutations, mainly because other protein truncating mutations are very rare.Taken together, due to some conflicts and uncertainties in literature about the variants pathogenicity, a classification of VUS is appropriate at this time.
Invitae RCV000005623 SCV000649856 likely pathogenic Common variable immunodeficiency 2 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 104 of the TNFRSF13B protein (p.Cys104Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs34557412, ExAC 0.5%). This variant has been reported in many individuals affected with common variable immunodeficiency (CVID) as homozygous, compound heterozygous with other TNFRSF13B variants, and as a heterozygous variant (PMID: 16007087, 17392797, 22697072, 27123465, 24051380, 19779048). This variant has also been seen as heterozygous in multiple unaffected relatives, but studies on B cells of these relatives show impaired function compared to unaffected individuals without TNFRSF13B variants (PMID: 23237420, 24051380). A meta-analysis of 1,423 CVID patients and 4,225 controls showed that this variant is significantly enriched in CVID patients (PMID: 22884984). In addition, this variant has been seen to segregate with disease in multiple families, although it appears to have reduced penetrance (PMID: 16007087, 19779048, 22983507, 22697072, 22884984, 23237420). The TNFRSF13B gene is also known as TACI in the literature. ClinVar contains an entry for this variant (Variation ID: 5302). Experimental studies have shown that this missense change disrupts ligand binding with APRIL, impairs B-cell proliferation in response to stimulation, and reduces the expression of TNFRSF13B on the surface of B-cells (PMID: 16007087, 21419480, 23237420). Individuals who are heterozygous for p.Cys104Arg have an increased number of autoreactive B-cells in the bone marrow (PMID: 24051380). In addition, mouse models with this variant also show reduced immunoglobulin production upon stimulation (PMID: 20889194, 21458042). In summary, this variant is a rare missense change that has been seen to segregate in multiple CVID families and disrupts protein function. This evidence indicates that the variant is pathogenic, but given the frequency of this variant in unaffected individuals, additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
OMIM RCV000005623 SCV000025805 pathogenic Common variable immunodeficiency 2 2007-06-01 no assertion criteria provided literature only
OMIM RCV000005624 SCV000025806 pathogenic Immunoglobulin A deficiency 2 2007-06-01 no assertion criteria provided literature only
UCLA Clinical Genomics Center, UCLA RCV000005623 SCV000255489 likely pathogenic Common variable immunodeficiency 2 2014-07-15 criteria provided, single submitter clinical testing

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