ClinVar Miner

Submissions for variant NM_199242.3(UNC13D):c.335G>C (p.Cys112Ser)

gnomAD frequency: 0.00004  dbSNP: rs141540493
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001037027 SCV001200418 uncertain significance Familial hemophagocytic lymphohistiocytosis 3 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 112 of the UNC13D protein (p.Cys112Ser). This variant is present in population databases (rs141540493, gnomAD 0.007%). This missense change has been observed in individual(s) with autoimmune lymphoproliferative syndrome (PMID: 23840885). ClinVar contains an entry for this variant (Variation ID: 836007). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UNC13D protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects UNC13D function (PMID: 23840885). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002222659 SCV002500786 uncertain significance not specified 2022-03-30 criteria provided, single submitter clinical testing Variant summary: UNC13D c.335G>C (p.Cys112Ser) results in a non-conservative amino acid change located in the C2 domain (IPR000008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251516 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.335G>C has been reported in the literature in individuals affected with autoimmune lymphoproliferative syndrome and primary immunodeficiencies (Arico_2013, Gallo_2016). These reports do not provide unequivocal conclusions about association of the variant with Familial Hemophagocytic Lymphohistiocytosis. At least one functional study reports this variant has an impact on UNC13D protein function and results in increasing CD63 expression on the cell surface (Arico_2013). One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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