ClinVar Miner

Submissions for variant NM_012452.2(TNFRSF13B):c.604C>T (p.Arg202Cys) (rs143562358)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000756793 SCV000884706 uncertain significance not provided 2017-10-10 criteria provided, single submitter clinical testing The p.Arg202Cys variant (rs143562358) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. Another change at this position p.Arg202His has been reported in associated with common variable immunodeficiency (Salzer 2005). However, the p.Arg202His variant was later found in control populations and did no segregate with disease in patients with selective IgA deficiency (Pan-Hammarstrom 2007). The p.Arg202Cys variant is listed in the genome Aggregation Database (gnomAD) with an African population frequency of 0.13 percent (identified on 31 out of 24,002 chromosomes). The arginine at position 202 is weakly conserved (considering 10 species, Alamut v.2.10.0) and Rhesus and other species have cysteine at this position indicating this change may be evolutionarily tolerated. Computational analyses of the effects of the p.Arg202Cys variant on protein structure and function indicated a neutral effect (SIFT: tolerated, MutationTaster: polymorphism, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Arg202Cys variant with certainty.
Invitae RCV000801725 SCV000941517 uncertain significance Common variable immunodeficiency 2 2018-08-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 202 of the TNFRSF13B protein (p.Arg202Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs143562358, ExAC 0.1%). This variant has not been reported in the literature in individuals with TNFRSF13B-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.

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