ClinVar Miner

Submissions for variant NM_032977.3(CASP10):c.1216A>T (p.Ile406Leu) (rs80358239)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000440171 SCV000511682 likely benign not provided 2017-01-06 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000378446 SCV000426105 likely benign Autoimmune lymphoproliferative syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000538417 SCV000644013 uncertain significance Autoimmune lymphoproliferative syndrome, type 2A; Autoimmune lymphoproliferative syndrome type 2 2018-06-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 406 of the CASP10 protein (p.Ile406Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs80358239, ExAC 1.5%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in four members of the same family, including two members affected with autoimmune lymphoproliferative syndrome (ALPS) (PMID: 16446975). While the other two members of this family were asymptomatic, both had elevated numbers of peripheral double negative T cells (DNTs) and diminished T cell apoptosis in vitro, and one exhibited lymphadenopathy. This variant has also been observed in an unrelated individual with ALPS (PMID: 16446975) and in another unrelated individual with some features consistent with ALPS (PMID: 27378136). The latter individual's mother also carried this variant and was unaffected with normal numbers of DNTs. ClinVar contains an entry for this variant (Variation ID: 333435). An experimental study has shown that this missense change impairs apoptosis in a dominant negative manner (PMID:16446975). In summary, this variant has been reported in individuals affected with ALPS and has an effect on protein function in vitro. However, it has also been observed in unaffected family members and is found at high frequency in population databases, which suggests this variant may be a neutral polymorphism. At this time, however, reduced penetrance cannot be excluded. In the absence of large case-control studies and/or additional functional data, this variant has been classified as a Variant of Uncertain Significance.

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