ClinVar Miner

Submissions for variant NM_001083962.2(TCF4):c.1826T>C (p.Leu609Pro)

dbSNP: rs1057524821
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Total submissions: 2
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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 RCV001507045 SCV001711996 likely pathogenic Pitt-Hopkins syndrome 2021-03-26 reviewed by expert panel curation The p.Leu609Pro variant in TCF4 occurs in the de novo state (biological parentage confirmed) in an affected individual (PS2). The p.Leu609Pro variant occurs in the well-characterized basic Helix-Loop-Helix domain (bHLH) functional domain of TCF4 (PM1). The p.Leu609Pro variant in TCF4 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Leu609Pro variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PS2, PM1, PM2_supporting, PP3).
GeneDx RCV000418798 SCV000536543 likely pathogenic not provided 2017-02-06 criteria provided, single submitter clinical testing The L609P variant in the TCF4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L609P variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The L609P variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position [that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. The L609P variant is a strong candidate for a pathogenic variant.

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