ClinVar Miner

Submissions for variant NM_014797.3(ZBTB24):c.1222T>G (p.Cys408Gly)

gnomAD frequency: 0.00002  dbSNP: rs387907105
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV003237415 SCV002011674 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Invitae RCV000024091 SCV002159904 pathogenic Immunodeficiency-centromeric instability-facial anomalies syndrome 2 2023-11-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 408 of the ZBTB24 protein (p.Cys408Gly). This variant is present in population databases (rs387907105, gnomAD 0.004%). This missense change has been observed in individual(s) with Immunodeficiency-centromeric instability-facial anomalies syndrome (PMID: 21596365, 22786748, 25330735, 30987377). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31096). 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 ZBTB24 function (PMID: 31066130). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000024091 SCV002512014 pathogenic Immunodeficiency-centromeric instability-facial anomalies syndrome 2 2022-03-28 criteria provided, single submitter clinical testing Variant summary: ZBTB24 c.1222T>G (p.Cys408Gly) results in a non-conservative amino acid change located in the Zinc finger C2H2-type domain (IPR013087) 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 2e-05 in 251398 control chromosomes. c.1222T>G has been reported in the literature as homozygous and compound heterozygous genotypes in individuals affected with ICF Syndrome, Type 2 (example, de Greef_2011, Cerbone_2012, Toubiana_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, Wu_2019). The most pronounced variant effect results in significantly decreased (approximately 10%-<30% of normal) activity in regulation of CDCA7 promoter by ZBTB24 as a transcription factor. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM RCV000024091 SCV000045382 pathogenic Immunodeficiency-centromeric instability-facial anomalies syndrome 2 2011-06-10 no assertion criteria provided literature only

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