ClinVar Miner

Submissions for variant NM_052945.3(TNFRSF13C):c.62C>G (p.Pro21Arg) (rs77874543)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000648324 SCV000438947 benign Common variable immunodeficiency 4 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae RCV000648324 SCV000770140 likely benign Common variable immunodeficiency 4 2020-12-04 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000648324 SCV001159029 risk factor Common variable immunodeficiency 4 2020-06-28 criteria provided, single submitter clinical testing The TNFRSF13C (BAFF-R) c.62C>G; p.Pro21Arg variant (rs77874543; ClinVar ID: 341883) is reported in individuals with common variable immunodeficiency (CVID) (Losi 2005, Lougaris 2016, Pieper 2014). In vitro functional studies showed that heterozygous p.Pro21Arg variant caused impaired ligand-independent preassembly of BAFF-R proteins, resulting in reduced binding of BAFF ligand, decreased NF-kappaB activation in B cells, and decreased proliferation and IgM production by B cells (Pieper 2014). However, the p.Pro21Arg variant did not affect B cell counts or B cell subsets (Pieper 2014), unlike in CVID caused by a homozygous 24 base pair in-frame deletion of TNFRSF13C, which blocks B cell development at the stage of transitional B cells (Warnatz 2009). One study found the p.Pro21Arg variant in 10.2% of CVID patients and in 6.7% of healthy individuals, a small but statistically significant enrichment (Pieper 2014). The p.Pro21Arg (rs77874543) is listed in the Genome Aggregation Database with an overall frequency of 6.0% (5931/98894 alleles, including 221 homozygotes). Based on the available evidence, the p.Pro21Arg variant may contribute to CVID as a risk factor, possibly together with other genetic and/or environmental factors.

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