ClinVar Miner

Submissions for variant NM_001330588.2(TPP2):c.3074A>G (p.Glu1025Gly)

gnomAD frequency: 0.00016  dbSNP: rs199569052
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000820024 SCV000960716 uncertain significance Evans syndrome, immunodeficiency, and premature immunosenescence associated with tripeptidyl-peptidase II deficiency 2025-01-13 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1012 of the TPP2 protein (p.Glu1012Gly). This variant is present in population databases (rs199569052, gnomAD 0.02%). This missense change has been observed in individual(s) with multiple sclerosis (PMID: 30533531). ClinVar contains an entry for this variant (Variation ID: 662393). 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 tolerated. 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV002272371 SCV002557843 uncertain significance Immunodeficiency 78 with autoimmunity and developmental delay 2022-06-24 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with immunodeficiency 78 with autoimmunity and developmental delay (MIM#619220). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glutamic acid to glycine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (34 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been reported as a VUS, and observed in a heterozygous individual with mild nonprogressive multiple sclerosis with an alternative diagnosis in the same gene (ClinVar, PMID: 30533531). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics RCV002272371 SCV002775969 uncertain significance Immunodeficiency 78 with autoimmunity and developmental delay 2022-04-29 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV004792532 SCV005409633 uncertain significance not provided 2024-08-19 criteria provided, single submitter clinical testing BP4, PM2

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