ClinVar Miner

Submissions for variant NM_020661.4(AICDA):c.259T>C (p.Cys87Arg)

gnomAD frequency: 0.00001  dbSNP: rs762590894
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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 RCV000755797 SCV000883371 pathogenic not provided 2018-02-06 criteria provided, single submitter clinical testing The p.Cys87Arg variant (rs762590894) was reported in one homozygote female with hyper-IgM syndrome (Quartier 2010). A different variant at the same codon (p.Cys87Ser) has also been previously identified in patients with hyper-IgM syndrome (Durandy 2006, Silva 2010). In vitro functional studies showed that the cysteine at position 87 is required for catalytic activity, and AICDA protein with the p.Cys87Arg variant is unable to catalyze cytosine deamination (Mu 2012). This variant is listed in the Genome Aggregation Database (gnomAD) identified on two out of 246,194 chromosomes and all computation predictors indicate a deleterious effect on protein structure and function. Overall the p.Cys87Arg is considered to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001043961 SCV001207733 pathogenic Hyper-IgM syndrome type 2 2023-10-27 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 87 of the AICDA protein (p.Cys87Arg). This variant is present in population databases (rs762590894, gnomAD 0.0009%). This missense change has been observed in individuals with hyper-IgM syndrome (PMID: 14962793, 15358621). ClinVar contains an entry for this variant (Variation ID: 617969). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects AICDA function (PMID: 22715099, 24349193, 25025377). This variant disrupts the p.Cys87 amino acid residue in AICDA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 21192628, 22715099; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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