Submissions for variant NM_001083962.2(TCF4):c.1744C>T (p.Arg582Cys)

dbSNP: rs2047109965

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001300533	SCV004035180	likely pathogenic	Pitt-Hopkins syndrome	2023-08-23	reviewed by expert panel	curation	The p.Arg582Cys 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). The p.Arg582Cys variant occurs in the well-characterized basic Helix-Loop-Helix domain (bHLH) functional domain of the TCF4 (PM1). A pathogenic missense variant (p.R582P) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 22460224, PMID 26621827, PMID 20184619, internal database) (PM5). The p.Arg582Cys variant in TCF4 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with an unspecified neurodevelopmental disorder (PMID 33994118). The p.Arg582Cys variant has been observed in at least 2 individuals with clinical features of Pitt-Hopkins syndrome (PMID 33994118, internal database) (PS4_Supporting). In summary, the p.Arg582Cys variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM2_Supporting, PP3, PM1, PM5, PS4_Supporting).
Invitae	RCV001300533	SCV001489677	uncertain significance	Pitt-Hopkins syndrome	2020-02-21	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with TCF4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 582 of the TCF4 protein (p.Arg582Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine.
GeneDx	RCV002298925	SCV002587875	likely pathogenic	not provided	2022-04-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33994118)
Institute of Human Genetics, University of Leipzig Medical Center	RCV001300533	SCV003804647	likely pathogenic	Pitt-Hopkins syndrome	2023-01-31	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed) in an indiviudal with moderate ID but no other features of PTHS Criteria applied: PS2_MOD, PM1, PM5, PS4_SUP, PM2_SUP, PP3 At the affected amino acid position, another amino acid substitution is already described as pathogenic in the databases for disease-causing variants and in the literature (PM5, c.1745G>C; p.R582P, HGMD-ID: CM105053, Takano et al., 2010, PubMed: 20184619)