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NM_001083962.2(TCF4):c.1733G>A (p.Arg578His) AND Pitt-Hopkins syndrome

Germline classification:
Pathogenic (4 submissions)
Last evaluated:
Mar 26, 2021
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:
RCV000079458.22

Allele description [Variation Report for NM_001083962.2(TCF4):c.1733G>A (p.Arg578His)]

NM_001083962.2(TCF4):c.1733G>A (p.Arg578His)

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.1733G>A (p.Arg578His)
Other names:
p.R578H:CGT>CAT
HGVS:
  • NC_000018.10:g.55228993C>T
  • NG_011716.2:g.412001G>A
  • NM_001083962.2:c.1733G>AMANE SELECT
  • NM_001243226.3:c.2039G>A
  • NM_001243227.2:c.1661G>A
  • NM_001243228.2:c.1751G>A
  • NM_001243230.2:c.1712G>A
  • NM_001243231.2:c.1595G>A
  • NM_001243232.1:c.1520G>A
  • NM_001243233.2:c.1331G>A
  • NM_001243234.2:c.1253G>A
  • NM_001243235.2:c.1241G>A
  • NM_001243236.2:c.1241G>A
  • NM_001306207.1:c.1649G>A
  • NM_001306208.1:c.1508G>A
  • NM_001330604.3:c.1730G>A
  • NM_001330605.3:c.1343G>A
  • NM_001348211.2:c.1607G>A
  • NM_001348212.2:c.1331G>A
  • NM_001348213.2:c.1343G>A
  • NM_001348214.2:c.1238G>A
  • NM_001348215.2:c.1085G>A
  • NM_001348216.2:c.1253G>A
  • NM_001348217.1:c.1661G>A
  • NM_001348218.2:c.1661G>A
  • NM_001348219.2:c.1649G>A
  • NM_001348220.1:c.1646G>A
  • NM_001369567.1:c.1733G>A
  • NM_001369568.1:c.1733G>A
  • NM_001369569.1:c.1730G>A
  • NM_001369570.1:c.1730G>A
  • NM_001369571.1:c.1721G>A
  • NM_001369572.1:c.1721G>A
  • NM_001369573.1:c.1718G>A
  • NM_001369574.1:c.1718G>A
  • NM_001369575.1:c.1661G>A
  • NM_001369576.1:c.1658G>A
  • NM_001369577.1:c.1658G>A
  • NM_001369578.1:c.1658G>A
  • NM_001369579.1:c.1658G>A
  • NM_001369580.1:c.1658G>A
  • NM_001369581.1:c.1658G>A
  • NM_001369582.1:c.1649G>A
  • NM_001369583.1:c.1649G>A
  • NM_001369584.1:c.1646G>A
  • NM_001369585.1:c.1646G>A
  • NM_001369586.1:c.1664G>A
  • NM_003199.2:c.1721G>A
  • NM_003199.3:c.1721G>A
  • NP_001077431.1:p.Arg578His
  • NP_001230155.2:p.Arg680His
  • NP_001230156.1:p.Arg554His
  • NP_001230157.1:p.Arg584His
  • NP_001230159.1:p.Arg571His
  • NP_001230160.1:p.Arg532His
  • NP_001230161.1:p.Arg507His
  • NP_001230162.1:p.Arg444His
  • NP_001230163.1:p.Arg418His
  • NP_001230164.1:p.Arg414His
  • NP_001230165.1:p.Arg414His
  • NP_001293136.1:p.Arg550His
  • NP_001293137.1:p.Arg503His
  • NP_001317533.1:p.Arg577His
  • NP_001317534.1:p.Arg448His
  • NP_001335140.1:p.Arg536His
  • NP_001335141.1:p.Arg444His
  • NP_001335142.1:p.Arg448His
  • NP_001335143.1:p.Arg413His
  • NP_001335144.1:p.Arg362His
  • NP_001335145.1:p.Arg418His
  • NP_001335146.1:p.Arg554His
  • NP_001335147.1:p.Arg554His
  • NP_001335148.1:p.Arg550His
  • NP_001335149.1:p.Arg549His
  • NP_001356496.1:p.Arg578His
  • NP_001356497.1:p.Arg578His
  • NP_001356498.1:p.Arg577His
  • NP_001356499.1:p.Arg577His
  • NP_001356500.1:p.Arg574His
  • NP_001356501.1:p.Arg574His
  • NP_001356502.1:p.Arg573His
  • NP_001356503.1:p.Arg573His
  • NP_001356504.1:p.Arg554His
  • NP_001356505.1:p.Arg553His
  • NP_001356506.1:p.Arg553His
  • NP_001356507.1:p.Arg553His
  • NP_001356508.1:p.Arg553His
  • NP_001356509.1:p.Arg553His
  • NP_001356510.1:p.Arg553His
  • NP_001356511.1:p.Arg550His
  • NP_001356512.1:p.Arg550His
  • NP_001356513.1:p.Arg549His
  • NP_001356514.1:p.Arg549His
  • NP_001356515.1:p.Arg555His
  • NP_003190.1:p.Arg574His
  • NC_000018.9:g.52896224C>T
  • NM_001083962.1:c.1733G>A
  • NM_001083962.2(TCF4):c.1733G>AMANE SELECT
  • NM_001243226.2:c.2039G>A
Protein change:
R362H
Links:
dbSNP: rs121909123
NCBI 1000 Genomes Browser:
rs121909123
Molecular consequence:
  • NM_001083962.2:c.1733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243226.3:c.2039G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243227.2:c.1661G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243228.2:c.1751G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243230.2:c.1712G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243231.2:c.1595G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243232.1:c.1520G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243233.2:c.1331G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243234.2:c.1253G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243235.2:c.1241G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001243236.2:c.1241G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306207.1:c.1649G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001306208.1:c.1508G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330604.3:c.1730G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001330605.3:c.1343G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001348211.2:c.1607G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001348212.2:c.1331G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001348213.2:c.1343G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001348214.2:c.1238G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001348215.2:c.1085G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001348216.2:c.1253G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001348217.1:c.1661G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001348218.2:c.1661G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001348219.2:c.1649G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001348220.1:c.1646G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369567.1:c.1733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369568.1:c.1733G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369569.1:c.1730G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369570.1:c.1730G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369571.1:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369572.1:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369573.1:c.1718G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369574.1:c.1718G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369575.1:c.1661G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369576.1:c.1658G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369577.1:c.1658G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369578.1:c.1658G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369579.1:c.1658G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369580.1:c.1658G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369581.1:c.1658G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369582.1:c.1649G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369583.1:c.1649G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369584.1:c.1646G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369585.1:c.1646G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369586.1:c.1664G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_003199.3:c.1721G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

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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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000586754Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Jan 6, 2017)
de novoclinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV000782334Center for Human Genetics, Inc, Center for Human Genetics, Inc
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Nov 1, 2016)
germlineclinical testing

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

SCV001234884Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jul 19, 2022)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV001712025ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
reviewed by expert panel

(ClinGen RettAS ACMG Specifications V1)
Pathogenic
(Mar 26, 2021)
germlinecuration

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedde novoyes1not providednot providednot providednot providedclinical testing
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing, curation

Citations

PubMed

Using medical exome sequencing to identify the causes of neurodevelopmental disorders: Experience of 2 clinical units and 216 patients.

Chérot E, Keren B, Dubourg C, Carré W, Fradin M, Lavillaureix A, Afenjar A, Burglen L, Whalen S, Charles P, Marey I, Heide S, Jacquette A, Heron D, Doummar D, Rodriguez D, Billette de Villemeur T, Moutard ML, Guët A, Xavier J, Périsse D, Cohen D, et al.

Clin Genet. 2018 Mar;93(3):567-576. doi: 10.1111/cge.13102. Epub 2017 Oct 4.

PubMed [citation]
PMID:
28708303

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753
See all PubMed Citations (7)

Details of each submission

From Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris, SCV000586754.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

Intellectual disability, severe; obesity; behavioural disorder

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1de novoyesnot providednot providednot provided1not providednot providednot provided

From Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782334.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001234884.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This missense change has been observed in individual(s) with Pitt-Hopkins syndrome (PMID: 18728071, 21671391, 29695756). 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 histidine, which is basic and polar, at codon 578 of the TCF4 protein (p.Arg578His). ClinVar contains an entry for this variant (Variation ID: 93542). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TCF4 function (PMID: 22460224). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0").

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV001712025.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcuration PubMed (2)

Description

The p.Arg578His variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt-Hopkins syndrome (PMID 18728071) (PP4). This variant appears to be de novo in this patient and has been reported in the de novo state (biological parentage unconfirmed) in at least two additional patients with Pitt-Hopkins syndrome (PMID 21671391) (PM6_strong, PS4_moderate). In vitro binding assays have shown that this variant impacts impacts protein function (PMID 22460224) (PS3_supporting). This variant is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg578His variant in TCF4 is absent from gnomAD (PM2_supporting). In summary, the Arg578His variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM1, PM2_supporting, PP3, PP4).

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 15, 2024