NM_001083962.2(TCF4):c.1738C>T (p.Arg580Trp) AND Pitt-Hopkins syndrome
- Germline classification:
- Pathogenic (8 submissions)
- Last evaluated:
- Mar 26, 2021
- Review status:
- 3 stars out of maximum of 4 starsreviewed by expert panel
- Somatic classification
of clinical impact: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Somatic classification
of oncogenicity: - None
- Review status:
- (0/4) 0 stars out of maximum of 4 starsno assertion criteria provided
- Record status:
- current
- Accession:
- RCV000007795.18
Allele description [Variation Report for NM_001083962.2(TCF4):c.1738C>T (p.Arg580Trp)]
NM_001083962.2(TCF4):c.1738C>T (p.Arg580Trp)
- 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.1738C>T (p.Arg580Trp)
- HGVS:
- NC_000018.10:g.55228988G>A
- NG_011716.2:g.412006C>T
- NM_001083962.1(TCF4):c.1738C>T
- NM_001083962.2:c.1738C>TMANE SELECT
- NM_001243226.3:c.2044C>T
- NM_001243227.2:c.1666C>T
- NM_001243228.2:c.1756C>T
- NM_001243230.2:c.1717C>T
- NM_001243231.2:c.1600C>T
- NM_001243232.1:c.1525C>T
- NM_001243233.2:c.1336C>T
- NM_001243234.2:c.1258C>T
- NM_001243235.2:c.1246C>T
- NM_001243236.2:c.1246C>T
- NM_001306207.1:c.1654C>T
- NM_001306208.1:c.1513C>T
- NM_001330604.3:c.1735C>T
- NM_001330605.3:c.1348C>T
- NM_001348211.2:c.1612C>T
- NM_001348212.2:c.1336C>T
- NM_001348213.2:c.1348C>T
- NM_001348214.2:c.1243C>T
- NM_001348215.2:c.1090C>T
- NM_001348216.2:c.1258C>T
- NM_001348217.1:c.1666C>T
- NM_001348218.2:c.1666C>T
- NM_001348219.2:c.1654C>T
- NM_001348220.1:c.1651C>T
- NM_001369567.1:c.1738C>T
- NM_001369568.1:c.1738C>T
- NM_001369569.1:c.1735C>T
- NM_001369570.1:c.1735C>T
- NM_001369571.1:c.1726C>T
- NM_001369572.1:c.1726C>T
- NM_001369573.1:c.1723C>T
- NM_001369574.1:c.1723C>T
- NM_001369575.1:c.1666C>T
- NM_001369576.1:c.1663C>T
- NM_001369577.1:c.1663C>T
- NM_001369578.1:c.1663C>T
- NM_001369579.1:c.1663C>T
- NM_001369580.1:c.1663C>T
- NM_001369581.1:c.1663C>T
- NM_001369582.1:c.1654C>T
- NM_001369583.1:c.1654C>T
- NM_001369584.1:c.1651C>T
- NM_001369585.1:c.1651C>T
- NM_001369586.1:c.1669C>T
- NM_003199.3:c.1726C>T
- NP_001077431.1:p.Arg580Trp
- NP_001230155.2:p.Arg682Trp
- NP_001230156.1:p.Arg556Trp
- NP_001230157.1:p.Arg586Trp
- NP_001230159.1:p.Arg573Trp
- NP_001230160.1:p.Arg534Trp
- NP_001230161.1:p.Arg509Trp
- NP_001230162.1:p.Arg446Trp
- NP_001230163.1:p.Arg420Trp
- NP_001230164.1:p.Arg416Trp
- NP_001230165.1:p.Arg416Trp
- NP_001293136.1:p.Arg552Trp
- NP_001293137.1:p.Arg505Trp
- NP_001317533.1:p.Arg579Trp
- NP_001317534.1:p.Arg450Trp
- NP_001335140.1:p.Arg538Trp
- NP_001335141.1:p.Arg446Trp
- NP_001335142.1:p.Arg450Trp
- NP_001335143.1:p.Arg415Trp
- NP_001335144.1:p.Arg364Trp
- NP_001335145.1:p.Arg420Trp
- NP_001335146.1:p.Arg556Trp
- NP_001335147.1:p.Arg556Trp
- NP_001335148.1:p.Arg552Trp
- NP_001335149.1:p.Arg551Trp
- NP_001356496.1:p.Arg580Trp
- NP_001356497.1:p.Arg580Trp
- NP_001356498.1:p.Arg579Trp
- NP_001356499.1:p.Arg579Trp
- NP_001356500.1:p.Arg576Trp
- NP_001356501.1:p.Arg576Trp
- NP_001356502.1:p.Arg575Trp
- NP_001356503.1:p.Arg575Trp
- NP_001356504.1:p.Arg556Trp
- NP_001356505.1:p.Arg555Trp
- NP_001356506.1:p.Arg555Trp
- NP_001356507.1:p.Arg555Trp
- NP_001356508.1:p.Arg555Trp
- NP_001356509.1:p.Arg555Trp
- NP_001356510.1:p.Arg555Trp
- NP_001356511.1:p.Arg552Trp
- NP_001356512.1:p.Arg552Trp
- NP_001356513.1:p.Arg551Trp
- NP_001356514.1:p.Arg551Trp
- NP_001356515.1:p.Arg557Trp
- NP_003190.1:p.Arg576Trp
- NC_000018.9:g.52896219G>A
- NM_001083962.1(TCF4):c.1738C>T
- NM_001083962.1:c.1738C>T
- NM_001243226.2:c.2044C>T
- p.Arg580Trp
This HGVS expression did not pass validation- Protein change:
- R364W; ARG576TRP
- Links:
- OMIM: 602272.0001; dbSNP: rs121909120
- NCBI 1000 Genomes Browser:
- rs121909120
- Molecular consequence:
- NM_001083962.2:c.1738C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001243226.3:c.2044C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001243227.2:c.1666C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001243228.2:c.1756C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001243230.2:c.1717C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001243231.2:c.1600C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001243232.1:c.1525C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001243233.2:c.1336C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001243234.2:c.1258C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001243235.2:c.1246C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001243236.2:c.1246C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001306207.1:c.1654C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001306208.1:c.1513C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001330604.3:c.1735C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001330605.3:c.1348C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001348211.2:c.1612C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001348212.2:c.1336C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001348213.2:c.1348C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001348214.2:c.1243C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001348215.2:c.1090C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001348216.2:c.1258C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001348217.1:c.1666C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001348218.2:c.1666C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001348219.2:c.1654C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001348220.1:c.1651C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369567.1:c.1738C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369568.1:c.1738C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369569.1:c.1735C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369570.1:c.1735C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369571.1:c.1726C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369572.1:c.1726C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369573.1:c.1723C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369574.1:c.1723C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369575.1:c.1666C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369576.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369577.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369578.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369579.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369580.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369581.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369582.1:c.1654C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369583.1:c.1654C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369584.1:c.1651C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369585.1:c.1651C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_001369586.1:c.1669C>T - missense variant - [Sequence Ontology: SO:0001583]
- NM_003199.3:c.1726C>T - 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
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000027996 | OMIM | no assertion criteria provided | Pathogenic (May 1, 2007) | germline | literature only | |
| SCV000898160 | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Aug 30, 2018) | de novo | clinical testing | |
| SCV001438319 | National Institute of Neuroscience, National Center of Neurology and Psychiatry | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | de novo | research | |
| SCV001586248 | Labcorp Genetics (formerly Invitae), Labcorp | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Jul 25, 2023) | germline | clinical testing | |
| SCV001653506 | Suma Genomics | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic | de novo | clinical testing | |
| SCV001712047 | ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel | reviewed by expert panel (ClinGen RettAS ACMG Specifications V1) | Pathogenic (Mar 26, 2021) | germline | curation | |
| SCV002576439 | Institute of Human Genetics, University of Leipzig Medical Center | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Aug 29, 2022) | de novo | clinical testing | |
| SCV004848872 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Nov 15, 2022) | germline | clinical testing |
Summary from all submissions
| Ethnicity | Origin | Affected | Individuals | Families | Chromosomes tested | Number Tested | Family history | Method |
|---|---|---|---|---|---|---|---|---|
| not provided | de novo | yes | 1 | not provided | not provided | not provided | not provided | clinical testing, research |
| not provided | germline | not provided | not provided | not provided | not provided | not provided | not provided | literature only |
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing, curation |
Citations
PubMed
Pitt-Hopkins syndrome in two patients and further definition of the phenotype.
Peippo MM, Simola KO, Valanne LK, Larsen AT, Kähkönen M, Auranen MP, Ignatius J.
Clin Dysmorphol. 2006 Apr;15(2):47-54.
- PMID:
- 16531728
European combined analysis of the CTG18.1 and the ERDA1 CAG/CTG repeats in bipolar disorder.
Del-Favero J, Gestel SV, Børglum AD, Muir W, Ewald H, Mors O, Ivezic S, Oruc L, Adolfsson R, Blackwood D, Kruse T, Mendlewicz J, Schalling M, Van Broeckhoven C.
Eur J Hum Genet. 2002 Apr;10(4):276-80.
- PMID:
- 12032737
Details of each submission
From OMIM, SCV000027996.2
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | literature only | PubMed (4) |
Description
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.
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | not provided | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals, SCV000898160.1
| # | 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 | de novo | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From National Institute of Neuroscience, National Center of Neurology and Psychiatry, SCV001438319.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | research | PubMed (2) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | de novo | yes | not provided | not provided | not provided | 1 | not provided | not provided | not provided | |
From Labcorp Genetics (formerly Invitae), Labcorp, SCV001586248.4
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (6) |
Description
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).
| # | 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 Suma Genomics, SCV001653506.1
| # | 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 | de novo | yes | 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, SCV001712047.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | PubMed (1) |
Description
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).
| # | 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 Human Genetics, University of Leipzig Medical Center, SCV002576439.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
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
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | de novo | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004848872.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
Description
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.
| # | 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: Nov 10, 2024