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).
ClinVar Genomic variation as it relates to human health
NM_001083962.2(TCF4):c.1733G>A (p.Arg578His)
Germline
Top reviewed classifications are shown here.
Submission summary:
Reviewed by expert panel
Pathogenic
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001083962.2(TCF4):c.1733G>A (p.Arg578His)
Variation ID: 93542 Accession: VCV000093542.22
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 18q21.2 18: 55228993 (GRCh38) [ NCBI UCSC ] 18: 52896224 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
-
First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Jun 28, 2015 May 1, 2024 Mar 26, 2021 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001083962.2(TCF4):c.1733G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
missense NM_001083962.2:c.1733G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001077431.1:p.Arg578His missense NM_001243226.3:c.2039G>A NP_001230155.2:p.Arg680His missense NM_001243227.2:c.1661G>A NP_001230156.1:p.Arg554His missense NM_001243228.2:c.1751G>A NP_001230157.1:p.Arg584His missense NM_001243230.2:c.1712G>A NP_001230159.1:p.Arg571His missense NM_001243231.2:c.1595G>A NP_001230160.1:p.Arg532His missense NM_001243232.1:c.1520G>A NP_001230161.1:p.Arg507His missense NM_001243233.2:c.1331G>A NP_001230162.1:p.Arg444His missense NM_001243234.2:c.1253G>A NP_001230163.1:p.Arg418His missense NM_001243235.2:c.1241G>A NP_001230164.1:p.Arg414His missense NM_001243236.2:c.1241G>A NP_001230165.1:p.Arg414His missense NM_001306207.1:c.1649G>A NP_001293136.1:p.Arg550His missense NM_001306208.1:c.1508G>A NP_001293137.1:p.Arg503His missense NM_001330604.3:c.1730G>A NP_001317533.1:p.Arg577His missense NM_001330605.3:c.1343G>A NP_001317534.1:p.Arg448His missense NM_001348211.2:c.1607G>A NP_001335140.1:p.Arg536His missense NM_001348212.2:c.1331G>A NP_001335141.1:p.Arg444His missense NM_001348213.2:c.1343G>A NP_001335142.1:p.Arg448His missense NM_001348214.2:c.1238G>A NP_001335143.1:p.Arg413His missense NM_001348215.2:c.1085G>A NP_001335144.1:p.Arg362His missense NM_001348216.2:c.1253G>A NP_001335145.1:p.Arg418His missense NM_001348217.1:c.1661G>A NP_001335146.1:p.Arg554His missense NM_001348218.2:c.1661G>A NP_001335147.1:p.Arg554His missense NM_001348219.2:c.1649G>A NP_001335148.1:p.Arg550His missense NM_001348220.1:c.1646G>A NP_001335149.1:p.Arg549His missense NM_001369567.1:c.1733G>A NP_001356496.1:p.Arg578His missense NM_001369568.1:c.1733G>A NP_001356497.1:p.Arg578His missense NM_001369569.1:c.1730G>A NP_001356498.1:p.Arg577His missense NM_001369570.1:c.1730G>A NP_001356499.1:p.Arg577His missense NM_001369571.1:c.1721G>A NP_001356500.1:p.Arg574His missense NM_001369572.1:c.1721G>A NP_001356501.1:p.Arg574His missense NM_001369573.1:c.1718G>A NP_001356502.1:p.Arg573His missense NM_001369574.1:c.1718G>A NP_001356503.1:p.Arg573His missense NM_001369575.1:c.1661G>A NP_001356504.1:p.Arg554His missense NM_001369576.1:c.1658G>A NP_001356505.1:p.Arg553His missense NM_001369577.1:c.1658G>A NP_001356506.1:p.Arg553His missense NM_001369578.1:c.1658G>A NP_001356507.1:p.Arg553His missense NM_001369579.1:c.1658G>A NP_001356508.1:p.Arg553His missense NM_001369580.1:c.1658G>A NP_001356509.1:p.Arg553His missense NM_001369581.1:c.1658G>A NP_001356510.1:p.Arg553His missense NM_001369582.1:c.1649G>A NP_001356511.1:p.Arg550His missense NM_001369583.1:c.1649G>A NP_001356512.1:p.Arg550His missense NM_001369584.1:c.1646G>A NP_001356513.1:p.Arg549His missense NM_001369585.1:c.1646G>A NP_001356514.1:p.Arg549His missense NM_001369586.1:c.1664G>A NP_001356515.1:p.Arg555His missense NM_003199.2:c.1721G>A NM_003199.3:c.1721G>A NP_003190.1:p.Arg574His missense NC_000018.10:g.55228993C>T NC_000018.9:g.52896224C>T NG_011716.2:g.412001G>A - Protein change
- R578H, R680H, R413H, R448H, R503H, R536H, R574H, R554H, R555H, R571H, R573H, R418H, R532H, R549H, R550H, R553H, R362H, R414H, R444H, R507H, R577H, R584H
- Other names
-
p.R578H:CGT>CAT
- Canonical SPDI
- NC_000018.10:55228992:C:T
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
- -
- Links
Genes
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
|---|---|---|---|---|---|---|
| HI score
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
|||
| TCF4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
993 | 1220 | |
Conditions - Germline
| Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
|---|---|---|---|---|
| Pathogenic (4) |
reviewed by expert panel
|
Mar 26, 2021 | RCV000079458.24 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Dec 17, 2021 | RCV000189738.18 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV001003999.9 | |
|
TCF4-related disorder
|
Pathogenic (1) |
criteria provided, single submitter
|
Sep 8, 2022 | RCV003398670.5 |
| Pathogenic (1) |
criteria provided, single submitter
|
- | RCV003883128.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Sep 12, 2022 | RCV002515762.9 |
Submissions - Germline
| Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Mar 26, 2021)
|
reviewed by expert panel
Method: curation
|
Pitt-Hopkins syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
FDA Recognized Database
Accession: SCV001712025.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Comment:
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 … (more)
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). (less)
|
|
|
Pathogenic
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Pitt-Hopkins syndrome
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782334.1
First in ClinVar: Jul 07, 2018 Last updated: Jul 07, 2018 |
|
|
|
Pathogenic
(Apr 02, 2013)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000111337.8
First in ClinVar: Jan 17, 2014 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 2
Sex: mixed
|
|
|
Pathogenic
(Dec 17, 2021)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000243386.13
First in ClinVar: Aug 07, 2015 Last updated: Mar 04, 2023 |
Comment:
Published functional studies demonstrate that R578H causes a loss of DNA binding and transactivation activity, disrupting normal protein function (Sepp et al., 2012).; Not observed … (more)
Published functional studies demonstrate that R578H causes a loss of DNA binding and transactivation activity, disrupting normal protein function (Sepp et al., 2012).; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18728071, 21671391, 22460224, 26621827, 28708303, 29695756, 31105003, 29655203, 32581362, 32005694, 33726816) (less)
|
|
|
Pathogenic
(Jul 19, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pitt-Hopkins syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001234884.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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"). (less)
|
|
|
Likely pathogenic
(Sep 12, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003564413.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.1733G>A (p.R578H) alteration is located in exon 18 (coding exon 17) of the TCF4 gene. This alteration results from a G to A substitution … (more)
The c.1733G>A (p.R578H) alteration is located in exon 18 (coding exon 17) of the TCF4 gene. This alteration results from a G to A substitution at nucleotide position 1733, causing the arginine (R) at amino acid position 578 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the TCF4 c.1733G>A alteration was not observed, with coverage at this position. This variant has been identified in several individuals with clinical features of Pitt-Hopkins syndrome (Zweier, 2008; Marangi, 2011; Whalen, 2012; Mary, 2018; Lindy, 2018). This variant completely abrogated DNA binding for homodimers and severely impaired DNA binding for heterodimers (Sepp, 2012). The p.R578H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
|
|
|
Pathogenic
(Jan 06, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Pitt-Hopkins syndrome
Affected status: yes
Allele origin:
de novo
|
Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris
Accession: SCV000586754.1
First in ClinVar: Jun 28, 2015 Last updated: Jun 28, 2015 |
Comment:
Intellectual disability, severe; obesity; behavioural disorder
Number of individuals with the variant: 1
Age: 10-19 years
Sex: male
|
|
|
Pathogenic
(Sep 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
TCF4-related condition
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV004103363.1
First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023 |
Comment:
The TCF4 c.1733G>A variant is predicted to result in the amino acid substitution p.Arg578His. This variant was reported in an individual with Pitt-Hopkins syndrome, reported … (more)
The TCF4 c.1733G>A variant is predicted to result in the amino acid substitution p.Arg578His. This variant was reported in an individual with Pitt-Hopkins syndrome, reported as de novo in multiple cases (Zweier et al. 2008. PubMed ID: 18728071; Patient 34, Chérot et al. 2017. PubMed ID: 28708303; Mary et al. 2018. PubMed ID: 29695756; Patient S0706, Table S2, Dong et al. 2020. PubMed ID: 32005694). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Corneal dystrophy, Fuchs endothelial, 3
Pitt-Hopkins syndrome
Explanation for multiple conditions: Uncertain.
The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.
Affected status: yes
Allele origin:
de novo
|
Molecular Genetics Lab, CHRU Brest
Accession: SCV004697739.1
First in ClinVar: Mar 05, 2024 Last updated: Mar 05, 2024 |
|
|
|
Pathogenic
(-)
|
no assertion criteria provided
Method: research
|
Microcephaly
Affected status: yes
Allele origin:
unknown
|
NIHR Bioresource Rare Diseases, University of Cambridge
Accession: SCV001162043.1
First in ClinVar: Feb 27, 2020 Last updated: Feb 27, 2020 |
Number of individuals with the variant: 1
Sex: female
|
Comment:
Comment:
Published functional studies demonstrate that R578H causes a loss of DNA binding and transactivation activity, disrupting normal protein function (Sepp et al., 2012).; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18728071, 21671391, 22460224, 26621827, 28708303, 29695756, 31105003, 29655203, 32581362, 32005694, 33726816)
Comment:
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").
Comment:
The c.1733G>A (p.R578H) alteration is located in exon 18 (coding exon 17) of the TCF4 gene. This alteration results from a G to A substitution at nucleotide position 1733, causing the arginine (R) at amino acid position 578 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the TCF4 c.1733G>A alteration was not observed, with coverage at this position. This variant has been identified in several individuals with clinical features of Pitt-Hopkins syndrome (Zweier, 2008; Marangi, 2011; Whalen, 2012; Mary, 2018; Lindy, 2018). This variant completely abrogated DNA binding for homodimers and severely impaired DNA binding for heterodimers (Sepp, 2012). The p.R578H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
Intellectual disability, severe; obesity; behavioural disorder
Comment:
The TCF4 c.1733G>A variant is predicted to result in the amino acid substitution p.Arg578His. This variant was reported in an individual with Pitt-Hopkins syndrome, reported as de novo in multiple cases (Zweier et al. 2008. PubMed ID: 18728071; Patient 34, Chérot et al. 2017. PubMed ID: 28708303; Mary et al. 2018. PubMed ID: 29695756; Patient S0706, Table S2, Dong et al. 2020. PubMed ID: 32005694). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Germline Functional Evidence
| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Comment:
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).
Comment:
Published functional studies demonstrate that R578H causes a loss of DNA binding and transactivation activity, disrupting normal protein function (Sepp et al., 2012).; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 18728071, 21671391, 22460224, 26621827, 28708303, 29695756, 31105003, 29655203, 32581362, 32005694, 33726816)
Comment:
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").
Comment:
The c.1733G>A (p.R578H) alteration is located in exon 18 (coding exon 17) of the TCF4 gene. This alteration results from a G to A substitution at nucleotide position 1733, causing the arginine (R) at amino acid position 578 to be replaced by a histidine (H). Based on data from the Genome Aggregation Database (gnomAD), the TCF4 c.1733G>A alteration was not observed, with coverage at this position. This variant has been identified in several individuals with clinical features of Pitt-Hopkins syndrome (Zweier, 2008; Marangi, 2011; Whalen, 2012; Mary, 2018; Lindy, 2018). This variant completely abrogated DNA binding for homodimers and severely impaired DNA binding for heterodimers (Sepp, 2012). The p.R578H alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
Intellectual disability, severe; obesity; behavioural disorder
Comment:
The TCF4 c.1733G>A variant is predicted to result in the amino acid substitution p.Arg578His. This variant was reported in an individual with Pitt-Hopkins syndrome, reported as de novo in multiple cases (Zweier et al. 2008. PubMed ID: 18728071; Patient 34, Chérot et al. 2017. PubMed ID: 28708303; Mary et al. 2018. PubMed ID: 29695756; Patient S0706, Table S2, Dong et al. 2020. PubMed ID: 32005694). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole-genome sequencing of patients with rare diseases in a national health system. | Turro E | Nature | 2020 | PMID: 32581362 |
| Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis. | Mary L | European journal of human genetics : EJHG | 2018 | PMID: 29695756 |
| Diagnostic outcomes for genetic testing of 70 genes in 8565 patients with epilepsy and neurodevelopmental disorders. | Lindy AS | Epilepsia | 2018 | PMID: 29655203 |
| 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 | Human molecular genetics | 2012 | PMID: 22460224 |
| Novel comprehensive diagnostic strategy in Pitt-Hopkins syndrome: clinical score and further delineation of the TCF4 mutational spectrum. | Whalen S | Human mutation | 2012 | PMID: 22045651 |
| The Pitt-Hopkins syndrome: report of 16 new patients and clinical diagnostic criteria. | Marangi G | American journal of medical genetics. Part A | 2011 | PMID: 21671391 |
| Further delineation of Pitt-Hopkins syndrome: phenotypic and genotypic description of 16 novel patients. | Zweier C | Journal of medical genetics | 2008 | PMID: 18728071 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=TCF4 | - | - | - | - |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b545bd8e-c8f6-4437-a1d0-ce19966d9ce7 | - | - | - | - |
Text-mined citations for rs121909123 ...
HelpThese citations are identified by LitVar using
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Record last updated Nov 25, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.