ACMG criteria used to clasify this variant: PS4, PS2_MOD, PM2_SUP, PP3
ClinVar Genomic variation as it relates to human health
NM_001083962.2(TCF4):c.1732C>T (p.Arg578Cys)
Germline
Classification
Help
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
(5)
Help
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Pathogenic/Likely pathogenic
5
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001083962.2(TCF4):c.1732C>T (p.Arg578Cys)
Variation ID: 1343925 Accession: VCV001343925.7
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.2 18: 55228994 (GRCh38) [ NCBI UCSC ] 18: 52896225 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Mar 19, 2022 Sep 16, 2024 Jul 24, 2024 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001083962.2:c.1732C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001077431.1:p.Arg578Cys missense NM_001243226.3:c.2038C>T NP_001230155.2:p.Arg680Cys missense NM_001243227.2:c.1660C>T NP_001230156.1:p.Arg554Cys missense NM_001243228.2:c.1750C>T NP_001230157.1:p.Arg584Cys missense NM_001243230.2:c.1711C>T NP_001230159.1:p.Arg571Cys missense NM_001243231.2:c.1594C>T NP_001230160.1:p.Arg532Cys missense NM_001243232.1:c.1519C>T NP_001230161.1:p.Arg507Cys missense NM_001243233.2:c.1330C>T NP_001230162.1:p.Arg444Cys missense NM_001243234.2:c.1252C>T NP_001230163.1:p.Arg418Cys missense NM_001243235.2:c.1240C>T NP_001230164.1:p.Arg414Cys missense NM_001243236.2:c.1240C>T NP_001230165.1:p.Arg414Cys missense NM_001306207.1:c.1648C>T NP_001293136.1:p.Arg550Cys missense NM_001306208.1:c.1507C>T NP_001293137.1:p.Arg503Cys missense NM_001330604.3:c.1729C>T NP_001317533.1:p.Arg577Cys missense NM_001330605.3:c.1342C>T NP_001317534.1:p.Arg448Cys missense NM_001348211.2:c.1606C>T NP_001335140.1:p.Arg536Cys missense NM_001348212.2:c.1330C>T NP_001335141.1:p.Arg444Cys missense NM_001348213.2:c.1342C>T NP_001335142.1:p.Arg448Cys missense NM_001348214.2:c.1237C>T NP_001335143.1:p.Arg413Cys missense NM_001348215.2:c.1084C>T NP_001335144.1:p.Arg362Cys missense NM_001348216.2:c.1252C>T NP_001335145.1:p.Arg418Cys missense NM_001348217.1:c.1660C>T NP_001335146.1:p.Arg554Cys missense NM_001348218.2:c.1660C>T NP_001335147.1:p.Arg554Cys missense NM_001348219.2:c.1648C>T NP_001335148.1:p.Arg550Cys missense NM_001348220.1:c.1645C>T NP_001335149.1:p.Arg549Cys missense NM_001369567.1:c.1732C>T NP_001356496.1:p.Arg578Cys missense NM_001369568.1:c.1732C>T NP_001356497.1:p.Arg578Cys missense NM_001369569.1:c.1729C>T NP_001356498.1:p.Arg577Cys missense NM_001369570.1:c.1729C>T NP_001356499.1:p.Arg577Cys missense NM_001369571.1:c.1720C>T NP_001356500.1:p.Arg574Cys missense NM_001369572.1:c.1720C>T NP_001356501.1:p.Arg574Cys missense NM_001369573.1:c.1717C>T NP_001356502.1:p.Arg573Cys missense NM_001369574.1:c.1717C>T NP_001356503.1:p.Arg573Cys missense NM_001369575.1:c.1660C>T NP_001356504.1:p.Arg554Cys missense NM_001369576.1:c.1657C>T NP_001356505.1:p.Arg553Cys missense NM_001369577.1:c.1657C>T NP_001356506.1:p.Arg553Cys missense NM_001369578.1:c.1657C>T NP_001356507.1:p.Arg553Cys missense NM_001369579.1:c.1657C>T NP_001356508.1:p.Arg553Cys missense NM_001369580.1:c.1657C>T NP_001356509.1:p.Arg553Cys missense NM_001369581.1:c.1657C>T NP_001356510.1:p.Arg553Cys missense NM_001369582.1:c.1648C>T NP_001356511.1:p.Arg550Cys missense NM_001369583.1:c.1648C>T NP_001356512.1:p.Arg550Cys missense NM_001369584.1:c.1645C>T NP_001356513.1:p.Arg549Cys missense NM_001369585.1:c.1645C>T NP_001356514.1:p.Arg549Cys missense NM_001369586.1:c.1663C>T NP_001356515.1:p.Arg555Cys missense NM_003199.3:c.1720C>T NP_003190.1:p.Arg574Cys missense NC_000018.10:g.55228994G>A NC_000018.9:g.52896225G>A NG_011716.2:g.412000C>T - Protein change
- R362C, R413C, R414C, R418C, R444C, R448C, R503C, R507C, R532C, R536C, R549C, R550C, R553C, R554C, R555C, R571C, R573C, R574C, R577C, R578C, R584C, R680C
- Other names
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- Canonical SPDI
- NC_000018.10:55228993: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. |
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| TCF4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
986 | 1213 | |
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/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 24, 2024 | RCV001847470.5 | |
| Likely pathogenic (1) |
criteria provided, single submitter
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Jul 14, 2022 | RCV002463815.1 | |
| Pathogenic/Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Nov 27, 2023 | RCV003152773.3 |
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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Likely pathogenic
(Jul 14, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Global developmental delay
Affected status: yes
Allele origin:
germline
|
Human Genetics Bochum, Ruhr University Bochum
Accession: SCV002758632.1
First in ClinVar: Dec 11, 2022 Last updated: Dec 11, 2022 |
Comment:
ACMG criteria used to clasify this variant: PS4, PS2_MOD, PM2_SUP, PP3
|
|
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Likely pathogenic
(Feb 23, 2023)
|
criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins syndrome
Affected status: yes
Allele origin:
unknown
|
3billion
Accession: SCV003841828.1
First in ClinVar: Mar 18, 2023 Last updated: Mar 18, 2023 |
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which … (more)
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TCF4 related disorder (ClinVar ID: VCV001343925 / PMID: 22678594). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22678594, 34128147). Different missense changes at the same codon (p.Arg578His, p.Arg578Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007374, VCV000093542). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. (less)
Clinical Features:
Epileptic encephalopathy (present) , Infantile spasms (present) , Global developmental delay (present) , EEG abnormality (present) , Abnormal facial shape (present) , Macrotia (present) , … (more)
Epileptic encephalopathy (present) , Infantile spasms (present) , Global developmental delay (present) , EEG abnormality (present) , Abnormal facial shape (present) , Macrotia (present) , Thick vermilion border (present) (less)
|
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Likely pathogenic
(Feb 18, 2023)
|
criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
|
Revvity Omics, Revvity
Accession: SCV004238753.1
First in ClinVar: Feb 04, 2024 Last updated: Feb 04, 2024 |
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Pathogenic
(Nov 27, 2023)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins syndrome
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV004297852.1
First in ClinVar: Feb 14, 2024 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 578 of the TCF4 protein … (more)
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 578 of the TCF4 protein (p.Arg578Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Pitt-Hopkins syndrome (PMID: 22678594, 34128147). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1343925). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg578 amino acid residue in TCF4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18728071, 21671391, 22460224, 29695756). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jul 24, 2024)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002104474.3
First in ClinVar: Mar 19, 2022 Last updated: Sep 16, 2024 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33093012, 22678594, 34128147) (less)
|
Comment:
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TCF4 related disorder (ClinVar ID: VCV001343925 / PMID: 22678594). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22678594, 34128147). Different missense changes at the same codon (p.Arg578His, p.Arg578Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007374, VCV000093542). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 578 of the TCF4 protein (p.Arg578Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Pitt-Hopkins syndrome (PMID: 22678594, 34128147). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1343925). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg578 amino acid residue in TCF4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18728071, 21671391, 22460224, 29695756). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33093012, 22678594, 34128147)
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:
ACMG criteria used to clasify this variant: PS4, PS2_MOD, PM2_SUP, PP3
Comment:
The variant is not observed in the gnomAD v2.1.1 dataset. The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.95; 3Cnet: 1.00). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with TCF4 related disorder (ClinVar ID: VCV001343925 / PMID: 22678594). The variant has been observed in at least two similarly affected unrelated individuals (PMID: 22678594, 34128147). Different missense changes at the same codon (p.Arg578His, p.Arg578Pro) have been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000007374, VCV000093542). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Comment:
This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 578 of the TCF4 protein (p.Arg578Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Pitt-Hopkins syndrome (PMID: 22678594, 34128147). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1343925). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg578 amino acid residue in TCF4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18728071, 21671391, 22460224, 29695756). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 33093012, 22678594, 34128147)
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Recommendations by the ClinGen Rett/Angelman-like expert panel for gene-specific variant interpretation methods. | McKnight D | Human mutation | 2022 | PMID: 34837432 |
| Pitt-Hopkins syndrome: phenotypic and genotypic description of four unrelated patients and structural analysis of corresponding missense mutations. | Zhao T | Neurogenetics | 2021 | PMID: 34128147 |
| 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 |
| Proposal of a clinical score for the molecular test for Pitt-Hopkins syndrome. | Marangi G | American journal of medical genetics. Part A | 2012 | PMID: 22678594 |
| 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 |
| 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 |
Text-mined citations for rs2144406630 ...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 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.