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 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:
- RCV000079458.24
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
This HGVS expression did not pass validation- 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
Assertion and evidence details
| Submission Accession | Submitter | Review Status (Assertion method) | Clinical Significance (Last evaluated) | Origin | Method | Citations |
|---|---|---|---|---|---|---|
| SCV000586754 | Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Jan 6, 2017) | de novo | clinical testing | |
| SCV000782334 | Center for Human Genetics, Inc, Center for Human Genetics, Inc | criteria provided, single submitter (ACMG Guidelines, 2015) | Pathogenic (Nov 1, 2016) | germline | clinical testing | |
| SCV001234884 | Labcorp Genetics (formerly Invitae), Labcorp | criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) | Pathogenic (Jul 19, 2022) | germline | clinical testing | |
| SCV001712025 | 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 |
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 |
| not provided | germline | yes | not provided | not provided | not provided | not provided | not provided | clinical testing |
| not provided | germline | unknown | not provided | not provided | not provided | not provided | not provided | clinical testing, curation |
Citations
PubMed
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
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
Details of each submission
From Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris, SCV000586754.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | 1 | not provided | not provided | clinical testing | PubMed (2) |
Description
Intellectual disability, severe; obesity; behavioural disorder
| # | 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 Center for Human Genetics, Inc, Center for Human Genetics, Inc, SCV000782334.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical testing | PubMed (1) |
| # | Sample | Method | Observation | |||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences | |
| 1 | germline | yes | not provided | not provided | not provided | not provided | not provided | not provided | not provided | |
From Labcorp Genetics (formerly Invitae), Labcorp, SCV001234884.5
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | clinical 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").
| # | 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 ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel, SCV001712025.1
| # | Ethnicity | Individuals | Chromosomes Tested | Family History | Method | Citations |
|---|---|---|---|---|---|---|
| 1 | not provided | not provided | not provided | not provided | curation | 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).
| # | 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: Dec 7, 2024