rs121909120

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM6_StrongPS4_SupportingPM2_SupportingPS3_SupportingPP3PP4

This summary comes from the ClinGen Evidence Repository: 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). LINK:https://erepo.genome.network/evrepo/ui/classification/CA254160/MONDO:0012589/016

Frequency

Genomes: not found (cov: 32)

Consequence

TCF4
NM_001083962.2 missense

Scores

16

2

1

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 8.06

Variant links:

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]

TCF4 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PS3

For more information check the summary or visit ClinGen Evidence Repository.

PS4

For more information check the summary or visit ClinGen Evidence Repository.

PM1

For more information check the summary or visit ClinGen Evidence Repository.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

PM6

For more information check the summary or visit ClinGen Evidence Repository.

PP3

For more information check the summary or visit ClinGen Evidence Repository.

PP4

For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCF4	NM_001083962.2 linkuse as main transcript	c.1738C>T	p.Arg580Trp	missense_variant	18/20	ENST00000354452.8	NP_001077431.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8 linkuse as main transcript	c.1738C>T	p.Arg580Trp	missense_variant	18/20	5	NM_001083962.2	ENSP00000346440	P3	P15884-3

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

LINK: link

Submissions by phenotype

Pitt-Hopkins syndrome

Pathogenic:8

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, no assertion criteria provided	literature only	OMIM	May 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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	clinical testing	Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals	Aug 30, 2018	- -
Pathogenic, criteria provided, single submitter	research	National Institute of Neuroscience, National Center of Neurology and Psychiatry	-	- -
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, 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	Suma Genomics	-	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
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	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) -

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

DEOGEN2

Uncertain

0.50

.;D;D;.;D;D;D;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

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

MutationAssessor

Pathogenic

4.5

.;.;H;.;.;.;.;.;.;H;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

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

PROVEAN

Pathogenic

-7.6

.;.;D;.;.;.;.;.;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;.;D;.;D;D;D;.

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

.;.;D;.;.;.;.;.;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;.;D;.;D;D;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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

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