Submissions for variant NM_001083962.2(TCF4):c.1733G>A (p.Arg578His)

dbSNP: rs121909123

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000079458	SCV001712025	pathogenic	Pitt-Hopkins syndrome	2021-03-26	reviewed by expert panel	curation	The p.Arg578His variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt-Hopkins syndrome (PMID 18728071) (PP4). This variant appears to be de novo in this patient and has been reported in the de novo state (biological parentage unconfirmed) in at least two additional patients with Pitt-Hopkins syndrome (PMID 21671391) (PM6_strong, PS4_moderate). In vitro binding assays have shown that this variant impacts impacts protein function (PMID 22460224) (PS3_supporting). This variant is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg578His variant in TCF4 is absent from gnomAD (PM2_supporting). In summary, the Arg578His variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM1, PM2_supporting, PP3, PP4).
Eurofins Ntd Llc (ga)	RCV000189738	SCV000111337	pathogenic	not provided	2013-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000189738	SCV000243386	pathogenic	not provided	2021-12-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that R578H causes a loss of DNA binding and transactivation activity, disrupting normal protein function (Sepp et al., 2012).; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18728071, 21671391, 22460224, 26621827, 28708303, 29695756, 31105003, 29655203, 32581362, 32005694, 33726816)
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	RCV000079458	SCV000586754	pathogenic	Pitt-Hopkins syndrome	2017-01-06	criteria provided, single submitter	clinical testing	Intellectual disability, severe; obesity; behavioural disorder
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000079458	SCV000782334	pathogenic	Pitt-Hopkins syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000079458	SCV001234884	pathogenic	Pitt-Hopkins syndrome	2022-07-19	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TCF4 function (PMID: 22460224). 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"). ClinVar contains an entry for this variant (Variation ID: 93542). This missense change has been observed in individual(s) with Pitt-Hopkins syndrome (PMID: 18728071, 21671391, 29695756). In at least one individual the variant was observed to be de novo. This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 578 of the TCF4 protein (p.Arg578His).
Ambry Genetics	RCV002515762	SCV003564413	likely pathogenic	Inborn genetic diseases	2022-09-12	criteria provided, single submitter	clinical testing	The c.1733G>A (p.R578H) alteration is located in exon 18 (coding exon 17) of the TCF4 gene. This alteration results from a G to A substitution at nucleotide position 1733, causing the arginine (R) at amino acid position 578 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the TCF4 c.1733G>A alteration was not observed, with coverage at this position. This variant has been identified in several individuals with clinical features of Pitt-Hopkins syndrome (Zweier, 2008; Marangi, 2011; Whalen, 2012; Mary, 2018; Lindy, 2018). This variant completely abrogated DNA binding for homodimers and severely impaired DNA binding for heterodimers (Sepp, 2012). The p.R578H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398670	SCV004103363	pathogenic	TCF4-related disorder	2022-09-08	criteria provided, single submitter	clinical testing	The TCF4 c.1733G>A variant is predicted to result in the amino acid substitution p.Arg578His. This variant was reported in an individual with Pitt-Hopkins syndrome, reported as de novo in multiple cases (Zweier et al. 2008. PubMed ID: 18728071; Patient 34, Chérot et al. 2017. PubMed ID: 28708303; Mary et al. 2018. PubMed ID: 29695756; Patient S0706, Table S2, Dong et al. 2020. PubMed ID: 32005694). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Molecular Genetics Lab, CHRU Brest	RCV003883128	SCV004697739	pathogenic	Pitt-Hopkins syndrome; Corneal dystrophy, Fuchs endothelial, 3		criteria provided, single submitter	clinical testing
NIHR Bioresource Rare Diseases, University of Cambridge	RCV001003999	SCV001162043	pathogenic	Microcephaly		no assertion criteria provided	research