rs121909120

chr18-55228988-G-Achr18-55228988-G-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_001083962.2(TCF4):c.1738C>T(p.Arg580Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R580Q) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCF4 NM_001083962.2 missense
• Clinical Significance: Pathogenic reviewed by expert panel P:13
• Conservation: PhyloP100: 8.06

Genes affected

TCF4 (HGNC:11634): (transcription factor 4) This gene encodes transcription factor 4, a basic helix-loop-helix transcription factor. The encoded protein recognizes an Ephrussi-box ('E-box') binding site ('CANNTG') - a motif first identified in immunoglobulin enhancers. This gene is broadly expressed, and may play an important role in nervous system development. Defects in this gene are a cause of Pitt-Hopkins syndrome. In addition, an intronic CTG repeat normally numbering 10-37 repeat units can expand to >50 repeat units and cause Fuchs endothelial corneal dystrophy. Multiple alternatively spliced transcript variants that encode different proteins have been described. [provided by RefSeq, Jul 2016]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in NM_001083962.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr18-55228987-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7371.Status of the report is reviewed_by_expert_panel, 3 stars.
• PP2: Missense variant where missense usually causes diseases, TCF4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 18-55228988-G-A is Pathogenic according to our data. Variant chr18-55228988-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7370.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr18-55228988-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCF4	NM_001083962.2	c.1738C>T	p.Arg580Trp	missense_variant	18/20	ENST00000354452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCF4	ENST00000354452.8	c.1738C>T	p.Arg580Trp	missense_variant	18/20	5	NM_001083962.2	P3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

Submissions by phenotype

Pitt-Hopkins syndrome Pathogenic:8

Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 25, 2023	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). -
Pathogenic, criteria provided, single submitter	research	National Institute of Neuroscience, National Center of Neurology and Psychiatry	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Suma Genomics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 15, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Aug 29, 2022	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 -
Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	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). -
Pathogenic, criteria provided, single submitter	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 30, 2018	- -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 17, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Jul 28, 2020	PS2, PS3, PS4, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -

Severe intellectual deficiency Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Laboratory of Molecular Genetics, CHU Rennes

-

- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 02, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.59
Cadd	Pathogenic	34
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	1.0	D;.;.;.;D;D;D;D;D;D;.;D;.;D;D;D;D;D;.;D;.;D;D;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.97	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Pathogenic	0.90	D
Sift4G	Pathogenic	0.0	D;.;D;.;.;.;.;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	.;.;D;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.
Vest4		0.93
MutPred		0.93		.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of disorder (P = 0.0127);.;.;
MVP		0.97
MPC		2.5
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.98
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121909120; hg19: chr18-52896219; COSMIC: COSV61902134; COSMIC: COSV61902134;