ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.520C>T (p.Arg174Ter)

dbSNP: rs878853149
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Diagnostic Laboratory, Strasbourg University Hospital RCV000224478 SCV000281742 pathogenic Intellectual disability 2014-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000760378 SCV000890242 pathogenic not provided 2022-04-04 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 in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28807867, 22045651, 31278258, 30830316, 26993267, 25167861, 33084218, 31785789)
Labcorp Genetics (formerly Invitae), Labcorp RCV000795184 SCV000934628 pathogenic Pitt-Hopkins syndrome 2022-07-03 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg174*) in the TCF4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCF4 are known to be pathogenic (PMID: 18728071, 22045651). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 235853). This premature translational stop signal has been observed in individual(s) with Pitt-Hopkins syndrome (PMID: 26993267). This variant is not present in population databases (gnomAD no frequency).
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV000795184 SCV001366150 pathogenic Pitt-Hopkins syndrome 2018-10-25 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5.
CeGaT Center for Human Genetics Tuebingen RCV000760378 SCV002546019 pathogenic not provided 2022-04-01 criteria provided, single submitter clinical testing TCF4: PVS1, PM2, PS2:Supporting, PS4:Supporting
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224231 SCV003920543 pathogenic Pitt-Hopkins syndrome; Corneal dystrophy, Fuchs endothelial, 3 2022-02-08 criteria provided, single submitter clinical testing This variant has been reported in the literature in 7 individuals, including as a de novo variants in at least 3 individuals (Selected publications: Redin 2014 PMID: 25167861; Trump 2016 PMID: 26993267; Turner 2019 PMID: 31785789). This variant is not present in large control databases but is present in ClinVar, with multiple labs classifying it as pathogenic (Variation ID: 235853). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is predicted to cause a stopgain at this codon, resulting in protein truncation or loss of allelic expression through nonsense mediated mRNA decay. Loss of function variants are a known mechanism of disease for this gene (Bedeschi 2017 PMID: 28807867). In summary, this variant is classified as pathogenic.

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