NM_001083962.2(TCF4):c.1841C>T (p.Ala614Val) AND Pitt-Hopkins syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 12, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000705624.12

Allele description [Variation Report for NM_001083962.2(TCF4):c.1841C>T (p.Ala614Val)]

NM_001083962.2(TCF4):c.1841C>T (p.Ala614Val)

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.1841C>T (p.Ala614Val)

HGVS:

NC_000018.10:g.55228885G>A
NG_011716.2:g.412109C>T
NM_001083962.2:c.1841C>TMANE SELECT
NM_001243226.3:c.2147C>T
NM_001243227.2:c.1769C>T
NM_001243228.2:c.1859C>T
NM_001243230.2:c.1820C>T
NM_001243231.2:c.1703C>T
NM_001243232.1:c.1628C>T
NM_001243233.2:c.1439C>T
NM_001243234.2:c.1361C>T
NM_001243235.2:c.1349C>T
NM_001243236.2:c.1349C>T
NM_001306207.1:c.1757C>T
NM_001306208.1:c.1616C>T
NM_001330604.3:c.1838C>T
NM_001330605.3:c.1451C>T
NM_001348211.2:c.1715C>T
NM_001348212.2:c.1439C>T
NM_001348213.2:c.1451C>T
NM_001348214.2:c.1346C>T
NM_001348215.2:c.1193C>T
NM_001348216.2:c.1361C>T
NM_001348217.1:c.1769C>T
NM_001348218.2:c.1769C>T
NM_001348219.2:c.1757C>T
NM_001348220.1:c.1754C>T
NM_001369567.1:c.1841C>T
NM_001369568.1:c.1841C>T
NM_001369569.1:c.1838C>T
NM_001369570.1:c.1838C>T
NM_001369571.1:c.1829C>T
NM_001369572.1:c.1829C>T
NM_001369573.1:c.1826C>T
NM_001369574.1:c.1826C>T
NM_001369575.1:c.1769C>T
NM_001369576.1:c.1766C>T
NM_001369577.1:c.1766C>T
NM_001369578.1:c.1766C>T
NM_001369579.1:c.1766C>T
NM_001369580.1:c.1766C>T
NM_001369581.1:c.1766C>T
NM_001369582.1:c.1757C>T
NM_001369583.1:c.1757C>T
NM_001369584.1:c.1754C>T
NM_001369585.1:c.1754C>T
NM_001369586.1:c.1772C>T
NM_003199.3:c.1829C>T
NP_001077431.1:p.Ala614Val
NP_001230155.2:p.Ala716Val
NP_001230156.1:p.Ala590Val
NP_001230157.1:p.Ala620Val
NP_001230159.1:p.Ala607Val
NP_001230160.1:p.Ala568Val
NP_001230161.1:p.Ala543Val
NP_001230162.1:p.Ala480Val
NP_001230163.1:p.Ala454Val
NP_001230164.1:p.Ala450Val
NP_001230165.1:p.Ala450Val
NP_001293136.1:p.Ala586Val
NP_001293137.1:p.Ala539Val
NP_001317533.1:p.Ala613Val
NP_001317534.1:p.Ala484Val
NP_001335140.1:p.Ala572Val
NP_001335141.1:p.Ala480Val
NP_001335142.1:p.Ala484Val
NP_001335143.1:p.Ala449Val
NP_001335144.1:p.Ala398Val
NP_001335145.1:p.Ala454Val
NP_001335146.1:p.Ala590Val
NP_001335147.1:p.Ala590Val
NP_001335148.1:p.Ala586Val
NP_001335149.1:p.Ala585Val
NP_001356496.1:p.Ala614Val
NP_001356497.1:p.Ala614Val
NP_001356498.1:p.Ala613Val
NP_001356499.1:p.Ala613Val
NP_001356500.1:p.Ala610Val
NP_001356501.1:p.Ala610Val
NP_001356502.1:p.Ala609Val
NP_001356503.1:p.Ala609Val
NP_001356504.1:p.Ala590Val
NP_001356505.1:p.Ala589Val
NP_001356506.1:p.Ala589Val
NP_001356507.1:p.Ala589Val
NP_001356508.1:p.Ala589Val
NP_001356509.1:p.Ala589Val
NP_001356510.1:p.Ala589Val
NP_001356511.1:p.Ala586Val
NP_001356512.1:p.Ala586Val
NP_001356513.1:p.Ala585Val
NP_001356514.1:p.Ala585Val
NP_001356515.1:p.Ala591Val
NP_003190.1:p.Ala610Val
NC_000018.9:g.52896116G>A
NM_001083962.1:c.1841C>T

Protein change:

A398V

Links:

dbSNP: rs1568303352

NCBI 1000 Genomes Browser:

rs1568303352

Molecular consequence:

NM_001083962.2:c.1841C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243226.3:c.2147C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243227.2:c.1769C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243228.2:c.1859C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243230.2:c.1820C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243231.2:c.1703C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243232.1:c.1628C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243233.2:c.1439C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243234.2:c.1361C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243235.2:c.1349C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243236.2:c.1349C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306207.1:c.1757C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306208.1:c.1616C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330604.3:c.1838C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330605.3:c.1451C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348211.2:c.1715C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348212.2:c.1439C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348213.2:c.1451C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348214.2:c.1346C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348215.2:c.1193C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348216.2:c.1361C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348217.1:c.1769C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348218.2:c.1769C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348219.2:c.1757C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348220.1:c.1754C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369567.1:c.1841C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369568.1:c.1841C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369569.1:c.1838C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369570.1:c.1838C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369571.1:c.1829C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369572.1:c.1829C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369573.1:c.1826C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369574.1:c.1826C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369575.1:c.1769C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369576.1:c.1766C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369577.1:c.1766C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369578.1:c.1766C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369579.1:c.1766C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369580.1:c.1766C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369581.1:c.1766C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369582.1:c.1757C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369583.1:c.1757C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369584.1:c.1754C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369585.1:c.1754C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369586.1:c.1772C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003199.3:c.1829C>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; Mental retardation, wide mouth, distinctive facial features, and intermittent hyperventilation followed by apnea
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
SCV000834630	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 28, 2019)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22460224, 22777675, 26621827, 19235238, 29695756, 28492532
SCV004175740	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 12, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000834630

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 28, 2019)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV004175740

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 12, 2023)

germline

clinical testing

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

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

Citations

PubMed

Pitt-Hopkins syndrome-associated mutations in TCF4 lead to variable impairment of the transcription factor function ranging from hypomorphic to dominant-negative effects.

Sepp M, Pruunsild P, Timmusk T.

Hum Mol Genet. 2012 Jul 1;21(13):2873-88. doi: 10.1093/hmg/dds112. Epub 2012 Mar 28.

PubMed [citation]

PMID:: 22460224

Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome.

Forrest M, Chapman RM, Doyle AM, Tinsley CL, Waite A, Blake DJ.

Hum Mutat. 2012 Dec;33(12):1676-86. doi: 10.1002/humu.22160. Epub 2012 Jul 27.

PubMed [citation]

PMID:: 22777675

See all PubMed Citations (7)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000834630.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect TCF4 protein function (PMID: 22460224, 22777675, 26621827). This variant has been observed to be de novo in individuals affected with Pitt-Hopkins syndrome (PMID: 19235238, 29695756). This variant is also known as c.1823C>T (p.Ala610Val) in the literature. ClinVar contains an entry for this variant (Variation ID: 581714). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 614 of the TCF4 protein (p.Ala614Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine.

#	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 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV004175740.1

#	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

Last Updated: Sep 29, 2024

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