18-55228987-C-T

Position:

chr18-55228987-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS3_SupportingPP3PP4PS4_SupportingPM6_StrongPM2_SupportingPM1

This summary comes from the ClinGen Evidence Repository: The p.Arg580Gln variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 22045651, 17436254) (PM6_strong, PS4_supporting, PP4). Transcriptional reporter assay has shown that this variant impacts protein function (PMID 19235238) (PS3_supporting). The p.Arg580Gln variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg580Gln variant in TCF4 is classified as Pathogenic for autosomal dominant Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PS4_supporting, PP1, PP3, PP4). LINK:https://erepo.genome.network/evrepo/ui/classification/CA254162/MONDO:0012589/016

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TCF4
NM_001083962.2 missense

Scores

15

3

1

Clinical Significance

Pathogenic reviewed by expert panel P:9

Conservation

PhyloP100: 7.91

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 link	c.1739G>A	p.Arg580Gln	missense_variant	18/20	ENST00000354452.8	NP_001077431.1	P15884-3B3KVA4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCF4	ENST00000354452.8 link	c.1739G>A	p.Arg580Gln	missense_variant	18/20	5	NM_001083962.2	ENSP00000346440.3		P15884-3

Frequencies

GnomAD3 genomes

Cov.:

32

GnomAD4 exome

AF:

6.84e-7

AC:

1

AN:

1461876

Hom.:

0

Cov.:

31

AF XY:

0.00000138

AC XY:

1

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Pitt-Hopkins syndrome

Pathogenic:7

Pathogenic, reviewed by expert panel	curation	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	Mar 26, 2021	The p.Arg580Gln variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 22045651, 17436254) (PM6_strong, PS4_supporting, PP4). Transcriptional reporter assay has shown that this variant impacts protein function (PMID 19235238) (PS3_supporting). The p.Arg580Gln variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg580Gln variant in TCF4 is classified as Pathogenic for autosomal dominant Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PS4_supporting, PP1, PP3, PP4). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 15, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Pitt-Hopkins syndrome (MIM#610954; PMID: 34134113). Fuchs endothelial corneal dystrophy 3 (MIM#613267) is caused by a CTG repeat expansion (OMIM), with the mechanism unclear. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants (DECIPHER). (SP) 0703 - Another missense variant comparable to the one identified in this case has moderate previous evidence for pathogenicity. The p.(Arg580Trp) variant has been classified as pathogenic by an expert panel (ClinGen) as well as being classified as likely pathogenic or pathogenic by clinical laboratories in ClinVar. (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by an expert panel (ClinGen) as well as being classified as likely pathogenic or pathogenic by clinical laboratories in ClinVar. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Oct 27, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2023	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, 17436255). 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: 19235238). 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. ClinVar contains an entry for this variant (Variation ID: 7371). This variant is also known as R576Q. This missense change has been observed in individual(s) with Pitt-Hopkins syndrome (PMID: 17436254, 29318938). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs121909121, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 580 of the TCF4 protein (p.Arg580Gln). -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2007	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2018	The R580Q variant in the TCF4 gene has been reported previously, as both R580Q and R576Q due to alternate nomenclature, in the heterozygous state in multiple unrelated individuals with Pitt-Hopkins syndrome, most often as a de novo variant (Amiel et al., 2007; de Pontual et al., 2009; Whalen et al., 2012). The R580Q variant is not observed in large population cohorts (Lek et al., 2016). The R580Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Functional studies using the luciferase reporter assay, demonstrate that mutant TCF4 activity is significantly lower than TCF4 wild-type heterodimers, supporting a loss of function effect (de Pontual et al., 2009). We interpret R580Q as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TCF4: PS4, PM2, PM5, PP2, PP3, PP4, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

D

BayesDel_noAF

Pathogenic

0.59

CADD

Pathogenic

34

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.49

.;T;D;.;T;T;T;.;.;D;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.96

FATHMM_MKL

Pathogenic

0.97

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

0.77

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

1.0

D

MutationAssessor

Pathogenic

4.5

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

PrimateAI

Pathogenic

0.82

D

PROVEAN

Uncertain

-3.8

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

REVEL

Pathogenic

0.98

Sift

Uncertain

0.0010

.;.;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, 1.0

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

Vest4

0.94

MutPred

0.93

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;Loss of helix (P = 0.0376);.;.;

MVP

0.98

MPC

2.6

ClinPred

1.0

D

GERP RS

5.9

Varity_R

0.98

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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: rs121909121; hg19: chr18-52896218;