NM_001083962.2(TCF4):c.1741G>T (p.Val581Phe) AND Pitt-Hopkins syndrome

Germline classification:: Likely pathogenic (3 submissions)
Last evaluated:: Feb 18, 2022
Review status:: 3 stars out of maximum of 4 stars
reviewed by expert panel

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000147716.17

Allele description [Variation Report for NM_001083962.2(TCF4):c.1741G>T (p.Val581Phe)]

NM_001083962.2(TCF4):c.1741G>T (p.Val581Phe)

Gene:

TCF4:transcription factor 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q21.2

Genomic location:

Preferred name:

NM_001083962.2(TCF4):c.1741G>T (p.Val581Phe)

Other names:

NM_001083962.2(TCF4):c.1741G>T; p.Val581Phe

HGVS:

NC_000018.10:g.55228985C>A
NG_011716.2:g.412009G>T
NM_001083962.2:c.1741G>TMANE SELECT
NM_001243226.3:c.2047G>T
NM_001243227.2:c.1669G>T
NM_001243228.2:c.1759G>T
NM_001243230.2:c.1720G>T
NM_001243231.2:c.1603G>T
NM_001243232.1:c.1528G>T
NM_001243233.2:c.1339G>T
NM_001243234.2:c.1261G>T
NM_001243235.2:c.1249G>T
NM_001243236.2:c.1249G>T
NM_001306207.1:c.1657G>T
NM_001306208.1:c.1516G>T
NM_001330604.3:c.1738G>T
NM_001330605.3:c.1351G>T
NM_001348211.2:c.1615G>T
NM_001348212.2:c.1339G>T
NM_001348213.2:c.1351G>T
NM_001348214.2:c.1246G>T
NM_001348215.2:c.1093G>T
NM_001348216.2:c.1261G>T
NM_001348217.1:c.1669G>T
NM_001348218.2:c.1669G>T
NM_001348219.2:c.1657G>T
NM_001348220.1:c.1654G>T
NM_001369567.1:c.1741G>T
NM_001369568.1:c.1741G>T
NM_001369569.1:c.1738G>T
NM_001369570.1:c.1738G>T
NM_001369571.1:c.1729G>T
NM_001369572.1:c.1729G>T
NM_001369573.1:c.1726G>T
NM_001369574.1:c.1726G>T
NM_001369575.1:c.1669G>T
NM_001369576.1:c.1666G>T
NM_001369577.1:c.1666G>T
NM_001369578.1:c.1666G>T
NM_001369579.1:c.1666G>T
NM_001369580.1:c.1666G>T
NM_001369581.1:c.1666G>T
NM_001369582.1:c.1657G>T
NM_001369583.1:c.1657G>T
NM_001369584.1:c.1654G>T
NM_001369585.1:c.1654G>T
NM_001369586.1:c.1672G>T
NM_003199.3:c.1729G>T
NP_001077431.1:p.Val581Phe
NP_001230155.2:p.Val683Phe
NP_001230156.1:p.Val557Phe
NP_001230157.1:p.Val587Phe
NP_001230159.1:p.Val574Phe
NP_001230160.1:p.Val535Phe
NP_001230161.1:p.Val510Phe
NP_001230162.1:p.Val447Phe
NP_001230163.1:p.Val421Phe
NP_001230164.1:p.Val417Phe
NP_001230165.1:p.Val417Phe
NP_001293136.1:p.Val553Phe
NP_001293137.1:p.Val506Phe
NP_001317533.1:p.Val580Phe
NP_001317534.1:p.Val451Phe
NP_001335140.1:p.Val539Phe
NP_001335141.1:p.Val447Phe
NP_001335142.1:p.Val451Phe
NP_001335143.1:p.Val416Phe
NP_001335144.1:p.Val365Phe
NP_001335145.1:p.Val421Phe
NP_001335146.1:p.Val557Phe
NP_001335147.1:p.Val557Phe
NP_001335148.1:p.Val553Phe
NP_001335149.1:p.Val552Phe
NP_001356496.1:p.Val581Phe
NP_001356497.1:p.Val581Phe
NP_001356498.1:p.Val580Phe
NP_001356499.1:p.Val580Phe
NP_001356500.1:p.Val577Phe
NP_001356501.1:p.Val577Phe
NP_001356502.1:p.Val576Phe
NP_001356503.1:p.Val576Phe
NP_001356504.1:p.Val557Phe
NP_001356505.1:p.Val556Phe
NP_001356506.1:p.Val556Phe
NP_001356507.1:p.Val556Phe
NP_001356508.1:p.Val556Phe
NP_001356509.1:p.Val556Phe
NP_001356510.1:p.Val556Phe
NP_001356511.1:p.Val553Phe
NP_001356512.1:p.Val553Phe
NP_001356513.1:p.Val552Phe
NP_001356514.1:p.Val552Phe
NP_001356515.1:p.Val558Phe
NP_003190.1:p.Val577Phe
NC_000018.9:g.52896216C>A
NM_001083962.1:c.1741G>T

Protein change:

V365F

Links:

dbSNP: rs587784460

NCBI 1000 Genomes Browser:

rs587784460

Molecular consequence:

NM_001083962.2:c.1741G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243226.3:c.2047G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243227.2:c.1669G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243228.2:c.1759G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243230.2:c.1720G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243231.2:c.1603G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243232.1:c.1528G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243233.2:c.1339G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243234.2:c.1261G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243235.2:c.1249G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243236.2:c.1249G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306207.1:c.1657G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306208.1:c.1516G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330604.3:c.1738G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330605.3:c.1351G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348211.2:c.1615G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348212.2:c.1339G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348213.2:c.1351G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348214.2:c.1246G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348215.2:c.1093G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348216.2:c.1261G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348217.1:c.1669G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348218.2:c.1669G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348219.2:c.1657G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348220.1:c.1654G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369567.1:c.1741G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369568.1:c.1741G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369569.1:c.1738G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369570.1:c.1738G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369571.1:c.1729G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369572.1:c.1729G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369573.1:c.1726G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369574.1:c.1726G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369575.1:c.1669G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369576.1:c.1666G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369577.1:c.1666G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369578.1:c.1666G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369579.1:c.1666G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369580.1:c.1666G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369581.1:c.1666G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369582.1:c.1657G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369583.1:c.1657G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369584.1:c.1654G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369585.1:c.1654G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369586.1:c.1672G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003199.3:c.1729G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Pitt-Hopkins syndrome (PTHS)
Synonyms:: ENCEPHALOPATHY, SEVERE EPILEPTIC, WITH AUTONOMIC DYSFUNCTION; MENTAL RETARDATION, SYNDROMAL, WITH INTERMITTENT HYPERVENTILATION
Identifiers:: MONDO: MONDO:0012589; MedGen: C1970431; Orphanet: 2896; OMIM: 610954

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000195180	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2007)	Likely pathogenic (Feb 8, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000830986	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 23, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002540697	ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	reviewed by expert panel (ClinGen RettAS ACMG Specifications V2)	Likely pathogenic (Feb 18, 2022)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000195180

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2007)

Likely pathogenic
(Feb 8, 2013)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000830986

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 23, 2024)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002540697

ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel

reviewed by expert panel

(ClinGen RettAS ACMG Specifications V2)

Likely pathogenic
(Feb 18, 2022)

germline

curation

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee.

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group, Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9..

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Genetic Services Laboratory, University of Chicago, SCV000195180.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000830986.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 581 of the TCF4 protein (p.Val581Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TCF4-related conditions. ClinVar contains an entry for this variant (Variation ID: 160079). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TCF4 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV002540697.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

The p.Val581Phe variant in TCF4 is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651) (PM1). This variant is absent from gnomAD (PM2_supporting). The p.Val581Phe variant in TCF4 occurs in the de novo state (biological parentage unconfirmed) in an individual with delays, hypotonia, not walking, dysmorphic features (University of Chicago internal database) (PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Val581Phe variant in TCF4 has been observed in at least 2 individuals with neurodevelopmental phenotype (University of Chicago internal database, Invitae internal database) (PS4_supporting). In summary, the p.Val581Phe variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM1, PM2_supporting, PM6, PP3, PS4_supporting).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: May 16, 2025

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