Submissions for variant NM_001083962.2(TCF4):c.1738C>T (p.Arg580Trp)

dbSNP: rs121909120

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000007795	SCV001712047	pathogenic	Pitt-Hopkins syndrome	2021-03-26	reviewed by expert panel	curation	The p.Arg580Trp variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 17436254, 22045651) (PM6_strong, PS4_supporting, PP4). The p.Arg580Trp in TCF4 is absent from gnomAD (PM2_supporting). The p.Arg580Trp variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). In vitro binding assays have shown that this variant impacts protein function (PMID 22460224) (PS3_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.Arg580Trp variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PM2_supporting, PS4_supporting, PP3, PP4).
GeneDx	RCV000387138	SCV000329544	pathogenic	not provided	2023-03-17	criteria provided, single submitter	clinical testing	In vitro and in vivo functional studies indicate it alters protein localization and affects homo- and heterodimer formation, thereby inhibiting protein-protein interactions (Sepp et al., 2012; Forrest et al,. 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22460224, 29318938, 22777675, 17436254, 18781613, 26621827, 17436255, 16531728, 29655203, 31130284, 32369273, 33624935, 31785789, 35599849, 35719373)
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	RCV000007795	SCV000898160	pathogenic	Pitt-Hopkins syndrome	2018-08-30	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000387138	SCV001430911	pathogenic	not provided	2020-07-28	criteria provided, single submitter	clinical testing	PS2, PS3, PS4, PM2
National Institute of Neuroscience, National Center of Neurology and Psychiatry	RCV000007795	SCV001438319	pathogenic	Pitt-Hopkins syndrome		criteria provided, single submitter	research
Ambry Genetics	RCV001266245	SCV001444417	pathogenic	Inborn genetic diseases	2019-10-02	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000387138	SCV001447787	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000007795	SCV001586248	pathogenic	Pitt-Hopkins syndrome	2023-07-25	criteria provided, single submitter	clinical testing	Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TCF4 protein function. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg580 amino acid residue in TCF4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17436254, 19235238). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TCF4 function (PMID: 22460224, 22777675). ClinVar contains an entry for this variant (Variation ID: 7370). This variant is also known as c.1726C>T; p.R576W. This missense change has been observed in individual(s) with Pitt-Hopkins syndrome (PHS) (PMID: 17436254, 17436255). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 580 of the TCF4 protein (p.Arg580Trp).
Suma Genomics	RCV000007795	SCV001653506	pathogenic	Pitt-Hopkins syndrome		criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000007795	SCV002576439	pathogenic	Pitt-Hopkins syndrome	2022-08-29	criteria provided, single submitter	clinical testing	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM5, PS3_SUP, PM2_SUP, PP3
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000007795	SCV004848872	pathogenic	Pitt-Hopkins syndrome	2022-11-15	criteria provided, single submitter	clinical testing	The p.Arg580Trp variant in TCF4 has been reported in at least 6 individuals with Pitt-Hopkins syndrome, including 4 de novo occurrences, one of which with confirmed parentage (Amiel 2007 PMID: 17436254, Zweier 2007 PMID: 17436255, Giurgea 2008 PMID: 18781613, Marangi 2011 PMID: 21671391, Goodspeed 2018 PMID: 29318938, Abe-Hatano 2021 PMID: 33624935). It was absent from large population studies. In vitro and drosophila functional studies provide some evidence that this variant impacts protein function (Sepp 2012 PMID: 22460224, Forrest 2012 PMID: 22777675, Tamberg 2015 PMID: 26621827) and computational prediction tools and conservation analyses are consistent with pathogenicity. This variant occurs in the basic Helix-Loop-Helix domain (bHLH), which has been well described. Another variant involving this codon (p.Arg580Gln) has been identified in individuals with Pitt-Hopkins and is classified as pathogenic by the ClinGen-approved Rett and Angelman-like Disorders expert panel in ClinVar. Additionally, this variant was also classified as Pathogenic on March 26, 2021 by the expert panel (Variation ID 7370). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Pitt-Hopkins. ACMG/AMP Criteria applied: PM6_Strong, PS4, PM5, PM2_Supporting, PS3_Supporting, PP3.
OMIM	RCV000007795	SCV000027996	pathogenic	Pitt-Hopkins syndrome	2007-05-01	no assertion criteria provided	literature only
Laboratory of Molecular Genetics, CHU Rennes	RCV000415008	SCV000493081	likely pathogenic	Severe intellectual deficiency		no assertion criteria provided	clinical testing