ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.1741G>T (p.Val581Phe)

dbSNP: rs587784460
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel RCV000147716 SCV002540697 likely pathogenic Pitt-Hopkins syndrome 2022-02-18 reviewed by expert panel curation The p.Val581Phe variant in TCF4 is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651) (PM1). This variant is absent from gnomAD (PM2_supporting). The p.Val581Phe variant in TCF4 occurs in the de novo state (biological parentage unconfirmed) in an individual with delays, hypotonia, not walking, dysmorphic features (University of Chicago internal database) (PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Val581Phe variant in TCF4 has been observed in at least 2 individuals with neurodevelopmental phenotype (University of Chicago internal database, Invitae internal database) (PS4_supporting). In summary, the p.Val581Phe variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM1, PM2_supporting, PM6, PP3, PS4_supporting).
Genetic Services Laboratory, University of Chicago RCV000147716 SCV000195180 likely pathogenic Pitt-Hopkins syndrome 2013-02-08 criteria provided, single submitter clinical testing
Invitae RCV000147716 SCV000830986 uncertain significance Pitt-Hopkins syndrome 2018-06-24 criteria provided, single submitter clinical testing This variant has not been reported in the literature in individuals with TCF4-related disease. ClinVar contains an entry for this variant (Variation ID: 160079). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with phenylalanine at codon 581 of the TCF4 protein (p.Val581Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine.

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