ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.469C>T (p.Arg157Ter)

dbSNP: rs587784464
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Genetic Services Laboratory, University of Chicago RCV000147723 SCV000195188 pathogenic Pitt-Hopkins syndrome 2013-02-08 criteria provided, single submitter clinical testing
GeneDx RCV000484787 SCV000568371 pathogenic not provided 2023-01-10 criteria provided, single submitter clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18728071, 22460224, 30830316, 28807867, 24651015, 27535533, 36393831, 22670824)
Revvity Omics, Revvity RCV000484787 SCV004238377 pathogenic not provided 2023-03-06 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000147723 SCV005087140 pathogenic Pitt-Hopkins syndrome 2023-07-16 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Pitt-Hopkins syndrome (MIM#610954). Fuchs endothelial corneal dystrophy (MIM#613267) is only caused by expanded CTG repeats (OMIM), with the mechanism unclear. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic (ClinVar, LOVD) and observed in at least two de novo individuals with Pitt Hopkins syndrome (PMID: 22670824, PMID: 18728071). (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed, by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Gene Friend Way, National Innovation Center RCV003313939 SCV004013898 pathogenic Autism spectrum disorder 2023-07-28 no assertion criteria provided clinical testing Nonsense variant predicted to result in protein truncation or nonsense mediated decay. The loss-of-function is a known mechanism of disease. Individuals will exhibit developmental disorders. This variant is associated with the following publications: PMID: 18728071, 22460224, 30830316, 28807867, 24651015, 27535533, 36393831, 22670824). TCF4 gene variants have been associated with neuropsychiatric diseases such as schizophrenia, bipolar disorder, intellectual disability. TCF4 gene polymorphisms are linked to autism spectrum disorder (PMID: 36448207), Pitt-Hopkins Syndrome (PMID: 17478476, 17436254, 17436255, 728011).

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