The p.Arg580Trp variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 17436254, 22045651) (PM6_strong, PS4_supporting, PP4). The p.Arg580Trp in TCF4 is absent from gnomAD (PM2_supporting). The p.Arg580Trp variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). In vitro binding assays have shown that this variant impacts protein function (PMID 22460224) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg580Trp variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PM2_supporting, PS4_supporting, PP3, PP4).
ClinVar Genomic variation as it relates to human health
NM_001083962.2(TCF4):c.1738C>T (p.Arg580Trp)
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.1738C>T (p.Arg580Trp)
Variation ID: 7370 Accession: VCV000007370.21
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.2 18: 55228988 (GRCh38) [ NCBI UCSC ] 18: 52896219 (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 Dec 6, 2016 Apr 20, 2024 Mar 26, 2021 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001083962.2:c.1738C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001077431.1:p.Arg580Trp missense NM_001243226.3:c.2044C>T NP_001230155.2:p.Arg682Trp missense NM_001243227.2:c.1666C>T NP_001230156.1:p.Arg556Trp missense NM_001243228.2:c.1756C>T NP_001230157.1:p.Arg586Trp missense NM_001243230.2:c.1717C>T NP_001230159.1:p.Arg573Trp missense NM_001243231.2:c.1600C>T NP_001230160.1:p.Arg534Trp missense NM_001243232.1:c.1525C>T NP_001230161.1:p.Arg509Trp missense NM_001243233.2:c.1336C>T NP_001230162.1:p.Arg446Trp missense NM_001243234.2:c.1258C>T NP_001230163.1:p.Arg420Trp missense NM_001243235.2:c.1246C>T NP_001230164.1:p.Arg416Trp missense NM_001243236.2:c.1246C>T NP_001230165.1:p.Arg416Trp missense NM_001306207.1:c.1654C>T NP_001293136.1:p.Arg552Trp missense NM_001306208.1:c.1513C>T NP_001293137.1:p.Arg505Trp missense NM_001330604.3:c.1735C>T NP_001317533.1:p.Arg579Trp missense NM_001330605.3:c.1348C>T NP_001317534.1:p.Arg450Trp missense NM_001348211.2:c.1612C>T NP_001335140.1:p.Arg538Trp missense NM_001348212.2:c.1336C>T NP_001335141.1:p.Arg446Trp missense NM_001348213.2:c.1348C>T NP_001335142.1:p.Arg450Trp missense NM_001348214.2:c.1243C>T NP_001335143.1:p.Arg415Trp missense NM_001348215.2:c.1090C>T NP_001335144.1:p.Arg364Trp missense NM_001348216.2:c.1258C>T NP_001335145.1:p.Arg420Trp missense NM_001348217.1:c.1666C>T NP_001335146.1:p.Arg556Trp missense NM_001348218.2:c.1666C>T NP_001335147.1:p.Arg556Trp missense NM_001348219.2:c.1654C>T NP_001335148.1:p.Arg552Trp missense NM_001348220.1:c.1651C>T NP_001335149.1:p.Arg551Trp missense NM_001369567.1:c.1738C>T NP_001356496.1:p.Arg580Trp missense NM_001369568.1:c.1738C>T NP_001356497.1:p.Arg580Trp missense NM_001369569.1:c.1735C>T NP_001356498.1:p.Arg579Trp missense NM_001369570.1:c.1735C>T NP_001356499.1:p.Arg579Trp missense NM_001369571.1:c.1726C>T NP_001356500.1:p.Arg576Trp missense NM_001369572.1:c.1726C>T NP_001356501.1:p.Arg576Trp missense NM_001369573.1:c.1723C>T NP_001356502.1:p.Arg575Trp missense NM_001369574.1:c.1723C>T NP_001356503.1:p.Arg575Trp missense NM_001369575.1:c.1666C>T NP_001356504.1:p.Arg556Trp missense NM_001369576.1:c.1663C>T NP_001356505.1:p.Arg555Trp missense NM_001369577.1:c.1663C>T NP_001356506.1:p.Arg555Trp missense NM_001369578.1:c.1663C>T NP_001356507.1:p.Arg555Trp missense NM_001369579.1:c.1663C>T NP_001356508.1:p.Arg555Trp missense NM_001369580.1:c.1663C>T NP_001356509.1:p.Arg555Trp missense NM_001369581.1:c.1663C>T NP_001356510.1:p.Arg555Trp missense NM_001369582.1:c.1654C>T NP_001356511.1:p.Arg552Trp missense NM_001369583.1:c.1654C>T NP_001356512.1:p.Arg552Trp missense NM_001369584.1:c.1651C>T NP_001356513.1:p.Arg551Trp missense NM_001369585.1:c.1651C>T NP_001356514.1:p.Arg551Trp missense NM_001369586.1:c.1669C>T NP_001356515.1:p.Arg557Trp missense NM_003199.3:c.1726C>T NP_003190.1:p.Arg576Trp missense NC_000018.10:g.55228988G>A NC_000018.9:g.52896219G>A NG_011716.2:g.412006C>T - Protein change
- R576W, R580W, R682W, R364W, R505W, R534W, R552W, R557W, R420W, R446W, R509W, R555W, R573W, R575W, R579W, R415W, R416W, R450W, R538W, R551W, R556W, R586W
- Other names
- -
- Canonical SPDI
- NC_000018.10:55228987:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
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- 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 (8) |
reviewed by expert panel
|
Mar 26, 2021 | RCV000007795.18 | |
| Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 17, 2023 | RCV000387138.8 | |
| Likely pathogenic (1) |
no assertion criteria provided
|
- | RCV000415008.2 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Oct 2, 2019 | RCV001266245.3 |
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. |
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|---|---|---|---|---|---|
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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: SCV001712047.1 First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
Comment:
The p.Arg580Trp variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 17436254, … (more)
The p.Arg580Trp variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 17436254, 22045651) (PM6_strong, PS4_supporting, PP4). The p.Arg580Trp in TCF4 is absent from gnomAD (PM2_supporting). The p.Arg580Trp variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). In vitro binding assays have shown that this variant impacts protein function (PMID 22460224) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg580Trp variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PM2_supporting, PS4_supporting, PP3, PP4). (less)
|
|
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Pathogenic
(Oct 23, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
|
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001447787.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Microcephaly (present) , Global developmental delay (present) , Autistic behavior (present) , Short stature (present) , Seizure (present) , Strabismus (present)
Sex: male
|
|
|
Pathogenic
(Oct 02, 2019)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: yes
Allele origin:
germline
|
Ambry Genetics
Accession: SCV001444417.2
First in ClinVar: Nov 21, 2020 Last updated: Jan 07, 2023 |
Number of individuals with the variant: 1
Clinical Features:
Severe global developmental delay (present) , Muscular hypotonia (present) , Atrial septal defect (present) , Strabismus (present) , Astigmatism (present) , Esotropia (present) , Epicanthus … (more)
Severe global developmental delay (present) , Muscular hypotonia (present) , Atrial septal defect (present) , Strabismus (present) , Astigmatism (present) , Esotropia (present) , Epicanthus inversus (present) , Cryptorchidism (present) , Abnormality of vitamin B12 metabolism (present) , Polyhydramnios (present) , Oligohydramnios (present) (less)
Sex: male
Ethnicity/Population group: Caucasian /Hispanic
|
|
|
Pathogenic
(Nov 15, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pitt-Hopkins syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV004848872.1
First in ClinVar: Apr 20, 2024 Last updated: Apr 20, 2024 |
Comment:
The p.Arg580Trp variant in TCF4 has been reported in at least 6 individuals with Pitt-Hopkins syndrome, including 4 de novo occurrences, one of which with … (more)
The p.Arg580Trp variant in TCF4 has been reported in at least 6 individuals with Pitt-Hopkins syndrome, including 4 de novo occurrences, one of which with confirmed parentage (Amiel 2007 PMID: 17436254, Zweier 2007 PMID: 17436255, Giurgea 2008 PMID: 18781613, Marangi 2011 PMID: 21671391, Goodspeed 2018 PMID: 29318938, Abe-Hatano 2021 PMID: 33624935). It was absent from large population studies. In vitro and drosophila functional studies provide some evidence that this variant impacts protein function (Sepp 2012 PMID: 22460224, Forrest 2012 PMID: 22777675, Tamberg 2015 PMID: 26621827) and computational prediction tools and conservation analyses are consistent with pathogenicity. This variant occurs in the basic Helix-Loop-Helix domain (bHLH), which has been well described. Another variant involving this codon (p.Arg580Gln) has been identified in individuals with Pitt-Hopkins and is classified as pathogenic by the ClinGen-approved Rett and Angelman-like Disorders expert panel in ClinVar. Additionally, this variant was also classified as Pathogenic on March 26, 2021 by the expert panel (Variation ID 7370). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Pitt-Hopkins. ACMG/AMP Criteria applied: PM6_Strong, PS4, PM5, PM2_Supporting, PS3_Supporting, PP3. (less)
|
|
|
Pathogenic
(Aug 30, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Pitt-Hopkins syndrome
Affected status: yes
Allele origin:
de novo
|
Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals
Accession: SCV000898160.1
First in ClinVar: Apr 21, 2019 Last updated: Apr 21, 2019 |
|
|
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Pathogenic
(Jul 28, 2020)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center
Accession: SCV001430911.1
First in ClinVar: Aug 28, 2020 Last updated: Aug 28, 2020 |
Comment:
PS2, PS3, PS4, PM2
|
|
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Pathogenic
(-)
|
criteria provided, single submitter
Method: research
|
Pitt-Hopkins syndrome
Affected status: yes
Allele origin:
de novo
|
National Institute of Neuroscience, National Center of Neurology and Psychiatry
Accession: SCV001438319.1
First in ClinVar: Mar 12, 2021 Last updated: Mar 12, 2021 |
Number of individuals with the variant: 1
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Pitt-Hopkins syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
|
Suma Genomics
Accession: SCV001653506.1
First in ClinVar: Jun 08, 2021 Last updated: Jun 08, 2021 |
|
|
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Pathogenic
(Aug 29, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Pitt-Hopkins syndrome
Affected status: yes
Allele origin:
de novo
|
Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV002576439.1
First in ClinVar: Oct 01, 2022 Last updated: Oct 01, 2022 |
Comment:
This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM5, PS3_SUP, PM2_SUP, PP3
|
|
|
Pathogenic
(Mar 17, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329544.6
First in ClinVar: Dec 06, 2016 Last updated: Mar 26, 2023 |
Comment:
In vitro and in vivo functional studies indicate it alters protein localization and affects homo- and heterodimer formation, thereby inhibiting protein-protein interactions (Sepp et al., … (more)
In vitro and in vivo functional studies indicate it alters protein localization and affects homo- and heterodimer formation, thereby inhibiting protein-protein interactions (Sepp et al., 2012; Forrest et al,. 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22460224, 29318938, 22777675, 17436254, 18781613, 26621827, 17436255, 16531728, 29655203, 31130284, 32369273, 33624935, 31785789, 35599849, 35719373) (less)
|
|
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Pathogenic
(Jul 25, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
Pitt-Hopkins syndrome
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001586248.4
First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024 |
Comment:
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) … (more)
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. 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, 19235238). 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: 22460224, 22777675). ClinVar contains an entry for this variant (Variation ID: 7370). This variant is also known as c.1726C>T; p.R576W. This missense change has been observed in individual(s) with Pitt-Hopkins syndrome (PHS) (PMID: 17436254, 17436255). 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 tryptophan, which is neutral and slightly polar, at codon 580 of the TCF4 protein (p.Arg580Trp). (less)
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Pathogenic
(May 01, 2007)
|
no assertion criteria provided
Method: literature only
|
PITT-HOPKINS SYNDROME
Affected status: not provided
Allele origin:
germline
|
OMIM
Accession: SCV000027996.2
First in ClinVar: Apr 04, 2013 Last updated: Dec 24, 2018 |
Comment on evidence:
In 2 unrelated patients with Pitt-Hopkins syndrome (610954), Amiel et al. (2007) found a heterozygous 1726C-T transition in exon 18 of the TCF4 gene, resulting … (more)
In 2 unrelated patients with Pitt-Hopkins syndrome (610954), Amiel et al. (2007) found a heterozygous 1726C-T transition in exon 18 of the TCF4 gene, resulting in an arg576-to-trp (R576W) substitution. The mutation was found neither in the parent DNA nor in a panel of 338 control chromosomes. In a patient reported by Peippo et al. (2006), Zweier et al. (2007) found the same R576W missense mutation. Zweier et al. (2007) referred to the mutation as R576/580W. The findings were consistent with haploinsufficiency as the disease mechanism. By in vitro studies, de Pontual et al. (2009) demonstrated that the R576W and R576Q (602272.0002) mutants both had decreased transcriptional activity even when coexpressed with ASCL1 (100790) as heterodimers, consistent with a loss of TCF4 function. (less)
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Severe intellectual deficiency
Affected status: yes
Allele origin:
de novo
|
Laboratory of Molecular Genetics, CHU Rennes
Accession: SCV000493081.1
First in ClinVar: Jan 13, 2017 Last updated: Jan 13, 2017 |
Sex: female
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Comment:
Comment:
The p.Arg580Trp variant in TCF4 has been reported in at least 6 individuals with Pitt-Hopkins syndrome, including 4 de novo occurrences, one of which with confirmed parentage (Amiel 2007 PMID: 17436254, Zweier 2007 PMID: 17436255, Giurgea 2008 PMID: 18781613, Marangi 2011 PMID: 21671391, Goodspeed 2018 PMID: 29318938, Abe-Hatano 2021 PMID: 33624935). It was absent from large population studies. In vitro and drosophila functional studies provide some evidence that this variant impacts protein function (Sepp 2012 PMID: 22460224, Forrest 2012 PMID: 22777675, Tamberg 2015 PMID: 26621827) and computational prediction tools and conservation analyses are consistent with pathogenicity. This variant occurs in the basic Helix-Loop-Helix domain (bHLH), which has been well described. Another variant involving this codon (p.Arg580Gln) has been identified in individuals with Pitt-Hopkins and is classified as pathogenic by the ClinGen-approved Rett and Angelman-like Disorders expert panel in ClinVar. Additionally, this variant was also classified as Pathogenic on March 26, 2021 by the expert panel (Variation ID 7370). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Pitt-Hopkins. ACMG/AMP Criteria applied: PM6_Strong, PS4, PM5, PM2_Supporting, PS3_Supporting, PP3.
Comment:
PS2, PS3, PS4, PM2
Comment:
This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM5, PS3_SUP, PM2_SUP, PP3
Comment:
In vitro and in vivo functional studies indicate it alters protein localization and affects homo- and heterodimer formation, thereby inhibiting protein-protein interactions (Sepp et al., 2012; Forrest et al,. 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22460224, 29318938, 22777675, 17436254, 18781613, 26621827, 17436255, 16531728, 29655203, 31130284, 32369273, 33624935, 31785789, 35599849, 35719373)
Comment:
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. 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, 19235238). 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: 22460224, 22777675). ClinVar contains an entry for this variant (Variation ID: 7370). This variant is also known as c.1726C>T; p.R576W. This missense change has been observed in individual(s) with Pitt-Hopkins syndrome (PHS) (PMID: 17436254, 17436255). 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 tryptophan, which is neutral and slightly polar, at codon 580 of the TCF4 protein (p.Arg580Trp).
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.Arg580Trp variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 17436254, 22045651) (PM6_strong, PS4_supporting, PP4). The p.Arg580Trp in TCF4 is absent from gnomAD (PM2_supporting). The p.Arg580Trp variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). In vitro binding assays have shown that this variant impacts protein function (PMID 22460224) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg580Trp variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PM2_supporting, PS4_supporting, PP3, PP4).
Comment:
The p.Arg580Trp variant in TCF4 has been reported in at least 6 individuals with Pitt-Hopkins syndrome, including 4 de novo occurrences, one of which with confirmed parentage (Amiel 2007 PMID: 17436254, Zweier 2007 PMID: 17436255, Giurgea 2008 PMID: 18781613, Marangi 2011 PMID: 21671391, Goodspeed 2018 PMID: 29318938, Abe-Hatano 2021 PMID: 33624935). It was absent from large population studies. In vitro and drosophila functional studies provide some evidence that this variant impacts protein function (Sepp 2012 PMID: 22460224, Forrest 2012 PMID: 22777675, Tamberg 2015 PMID: 26621827) and computational prediction tools and conservation analyses are consistent with pathogenicity. This variant occurs in the basic Helix-Loop-Helix domain (bHLH), which has been well described. Another variant involving this codon (p.Arg580Gln) has been identified in individuals with Pitt-Hopkins and is classified as pathogenic by the ClinGen-approved Rett and Angelman-like Disorders expert panel in ClinVar. Additionally, this variant was also classified as Pathogenic on March 26, 2021 by the expert panel (Variation ID 7370). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Pitt-Hopkins. ACMG/AMP Criteria applied: PM6_Strong, PS4, PM5, PM2_Supporting, PS3_Supporting, PP3.
Comment:
PS2, PS3, PS4, PM2
Comment:
This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PS2_VSTR, PS4_MOD, PM1, PM5, PS3_SUP, PM2_SUP, PP3
Comment:
In vitro and in vivo functional studies indicate it alters protein localization and affects homo- and heterodimer formation, thereby inhibiting protein-protein interactions (Sepp et al., 2012; Forrest et al,. 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22460224, 29318938, 22777675, 17436254, 18781613, 26621827, 17436255, 16531728, 29655203, 31130284, 32369273, 33624935, 31785789, 35599849, 35719373)
Comment:
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. 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, 19235238). 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: 22460224, 22777675). ClinVar contains an entry for this variant (Variation ID: 7370). This variant is also known as c.1726C>T; p.R576W. This missense change has been observed in individual(s) with Pitt-Hopkins syndrome (PHS) (PMID: 17436254, 17436255). 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 tryptophan, which is neutral and slightly polar, at codon 580 of the TCF4 protein (p.Arg580Trp).
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Whole genome sequencing of 45 Japanese patients with intellectual disability. | Abe-Hatano C | American journal of medical genetics. Part A | 2021 | PMID: 33624935 |
| Pitt-Hopkins Syndrome: A Review of Current Literature, Clinical Approach, and 23-Patient Case Series. | Goodspeed K | Journal of child neurology | 2018 | PMID: 29318938 |
| Introducing Pitt-Hopkins syndrome-associated mutations of TCF4 to Drosophila daughterless. | Tamberg L | Biology open | 2015 | PMID: 26621827 |
| Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome. | Forrest M | Human mutation | 2012 | PMID: 22777675 |
| 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 |
| Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome. | de Pontual L | Human mutation | 2009 | PMID: 19235238 |
| Haploinsufficiency of TCF4 causes syndromal mental retardation with intermittent hyperventilation (Pitt-Hopkins syndrome). | Zweier C | American journal of human genetics | 2007 | PMID: 17436255 |
| Mutations in TCF4, encoding a class I basic helix-loop-helix transcription factor, are responsible for Pitt-Hopkins syndrome, a severe epileptic encephalopathy associated with autonomic dysfunction. | Amiel J | American journal of human genetics | 2007 | PMID: 17436254 |
| Pitt-Hopkins syndrome in two patients and further definition of the phenotype. | Peippo MM | Clinical dysmorphology | 2006 | PMID: 16531728 |
| European combined analysis of the CTG18.1 and the ERDA1 CAG/CTG repeats in bipolar disorder. | Del-Favero J | European journal of human genetics : EJHG | 2002 | PMID: 12032737 |
| https://erepo.clinicalgenome.org/evrepo/ui/interpretation/b4b4e028-4434-4362-a57e-8a50ad94182f | - | - | - | - |
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Text-mined citations for rs121909120 ...
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Record last updated Nov 10, 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.