ClinVar Genomic variation as it relates to human health
NM_001083962.2(TCF4):c.1876C>T (p.Arg626Ter)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001083962.2(TCF4):c.1876C>T (p.Arg626Ter)
Variation ID: 430016 Accession: VCV000430016.14
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.2 18: 55228850 (GRCh38) [ NCBI UCSC ] 18: 52896081 (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 Jul 2, 2017 May 1, 2024 Oct 4, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001083962.2:c.1876C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001077431.1:p.Arg626Ter nonsense NM_001243226.3:c.2182C>T NP_001230155.2:p.Arg728Ter nonsense NM_001243227.2:c.1804C>T NP_001230156.1:p.Arg602Ter nonsense NM_001243228.2:c.1894C>T NP_001230157.1:p.Arg632Ter nonsense NM_001243230.2:c.1855C>T NP_001230159.1:p.Arg619Ter nonsense NM_001243231.2:c.1738C>T NP_001230160.1:p.Arg580Ter nonsense NM_001243232.1:c.1663C>T NP_001230161.1:p.Arg555Ter nonsense NM_001243233.2:c.1474C>T NP_001230162.1:p.Arg492Ter nonsense NM_001243234.2:c.1396C>T NP_001230163.1:p.Arg466Ter nonsense NM_001243235.2:c.1384C>T NP_001230164.1:p.Arg462Ter nonsense NM_001243236.2:c.1384C>T NP_001230165.1:p.Arg462Ter nonsense NM_001306207.1:c.1792C>T NP_001293136.1:p.Arg598Ter nonsense NM_001306208.1:c.1651C>T NP_001293137.1:p.Arg551Ter nonsense NM_001330604.3:c.1873C>T NP_001317533.1:p.Arg625Ter nonsense NM_001330605.3:c.1486C>T NP_001317534.1:p.Arg496Ter nonsense NM_001348211.2:c.1750C>T NP_001335140.1:p.Arg584Ter nonsense NM_001348212.2:c.1474C>T NP_001335141.1:p.Arg492Ter nonsense NM_001348213.2:c.1486C>T NP_001335142.1:p.Arg496Ter nonsense NM_001348214.2:c.1381C>T NP_001335143.1:p.Arg461Ter nonsense NM_001348215.2:c.1228C>T NP_001335144.1:p.Arg410Ter nonsense NM_001348216.2:c.1396C>T NP_001335145.1:p.Arg466Ter nonsense NM_001348217.1:c.1804C>T NP_001335146.1:p.Arg602Ter nonsense NM_001348218.2:c.1804C>T NP_001335147.1:p.Arg602Ter nonsense NM_001348219.2:c.1792C>T NP_001335148.1:p.Arg598Ter nonsense NM_001348220.1:c.1789C>T NP_001335149.1:p.Arg597Ter nonsense NM_001369567.1:c.1876C>T NP_001356496.1:p.Arg626Ter nonsense NM_001369568.1:c.1876C>T NP_001356497.1:p.Arg626Ter nonsense NM_001369569.1:c.1873C>T NP_001356498.1:p.Arg625Ter nonsense NM_001369570.1:c.1873C>T NP_001356499.1:p.Arg625Ter nonsense NM_001369571.1:c.1864C>T NP_001356500.1:p.Arg622Ter nonsense NM_001369572.1:c.1864C>T NP_001356501.1:p.Arg622Ter nonsense NM_001369573.1:c.1861C>T NP_001356502.1:p.Arg621Ter nonsense NM_001369574.1:c.1861C>T NP_001356503.1:p.Arg621Ter nonsense NM_001369575.1:c.1804C>T NP_001356504.1:p.Arg602Ter nonsense NM_001369576.1:c.1801C>T NP_001356505.1:p.Arg601Ter nonsense NM_001369577.1:c.1801C>T NP_001356506.1:p.Arg601Ter nonsense NM_001369578.1:c.1801C>T NP_001356507.1:p.Arg601Ter nonsense NM_001369579.1:c.1801C>T NP_001356508.1:p.Arg601Ter nonsense NM_001369580.1:c.1801C>T NP_001356509.1:p.Arg601Ter nonsense NM_001369581.1:c.1801C>T NP_001356510.1:p.Arg601Ter nonsense NM_001369582.1:c.1792C>T NP_001356511.1:p.Arg598Ter nonsense NM_001369583.1:c.1792C>T NP_001356512.1:p.Arg598Ter nonsense NM_001369584.1:c.1789C>T NP_001356513.1:p.Arg597Ter nonsense NM_001369585.1:c.1789C>T NP_001356514.1:p.Arg597Ter nonsense NM_001369586.1:c.1807C>T NP_001356515.1:p.Arg603Ter nonsense NM_003199.3:c.1864C>T NP_003190.1:p.Arg622Ter nonsense NC_000018.10:g.55228850G>A NC_000018.9:g.52896081G>A NG_011716.2:g.412144C>T - Protein change
- R626*, R462*, R551*, R584*, R597*, R601*, R603*, R625*, R632*, R728*, R466*, R619*, R621*, R622*, R410*, R496*, R580*, R602*, R461*, R492*, R555*, R598*
- Other names
- p.Arg728Ter
- Canonical SPDI
- NC_000018.10:55228849:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- protein truncation Variation Ontology [VariO:0015]
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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
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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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
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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 |
959 | 1184 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Oct 4, 2023 | RCV000493014.6 | |
Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 30, 2022 | RCV000660298.9 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 14, 2023 | RCV003159600.2 |
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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Likely pathogenic
(Nov 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins syndrome
Affected status: yes
Allele origin:
germline
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Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000782335.1
First in ClinVar: Jul 09, 2018 Last updated: Jul 09, 2018 |
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Pathogenic
(Oct 23, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
(Unknown mechanism)
Affected status: yes
Allele origin:
germline
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Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen
Accession: SCV001446521.1
First in ClinVar: Nov 28, 2020 Last updated: Nov 28, 2020 |
Clinical Features:
Hypotonia (present) , Global developmental delay (present) , Absent speech (present) , Difficulty walking (present) , Sleep abnormality (present) , Hypertelorism (present) , Small hand … (more)
Hypotonia (present) , Global developmental delay (present) , Absent speech (present) , Difficulty walking (present) , Sleep abnormality (present) , Hypertelorism (present) , Small hand (present) , Motor stereotypies (present) , Abnormality of the mouth (present) (less)
Sex: female
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Pathogenic
(Oct 04, 2023)
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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: SCV000582727.7
First in ClinVar: Jul 02, 2017 Last updated: Nov 25, 2023 |
Comment:
Not observed in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 46 amino acids are … (more)
Not observed in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 46 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 22045651, 22460224, 29604340, 31440721) (less)
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Pathogenic
(Sep 30, 2022)
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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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Invitae
Accession: SCV000819174.4
First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024 |
Comment:
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430016). This premature translational stop signal … (more)
For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430016). This premature translational stop signal has been observed in individual(s) with Pitt–Hopkins Syndrome (PMID: 22045651). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg626*) in the TCF4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCF4 are known to be pathogenic (PMID: 18728071, 22045651). (less)
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Pathogenic
(Dec 23, 2020)
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criteria provided, single submitter
Method: research
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Pitt-Hopkins syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
de novo
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002762860.1
First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022 |
Comment:
A heterozygous nonsense variation in exon 19 of the TCF4 gene that results in a stop codon and premature truncation of the protein at codon … (more)
A heterozygous nonsense variation in exon 19 of the TCF4 gene that results in a stop codon and premature truncation of the protein at codon 728 was detected. The observed variant c.2182C>T (p.Arg728Ter) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. Segregation analysis showed this variant to be de novo. In summary, the variant meets our criteria to be classified as a pathogenic variant. (less)
Clinical Features:
Umbilical hernia (present) , Seizure (present) , Cyanosis (present) , Wide nose (present) , Low-set ears (present) , Lower limb spasticity (present) , Tip-toe gait … (more)
Umbilical hernia (present) , Seizure (present) , Cyanosis (present) , Wide nose (present) , Low-set ears (present) , Lower limb spasticity (present) , Tip-toe gait (present) , Hyperactivity (present) , Impaired social interactions (present) , Recurrent hand flapping (present) , Pain insensitivity (present) , Autistic behavior (present) , Profound global developmental delay (present) (less)
Age: 0-9 years
Sex: female
Ethnicity/Population group: Hindu
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Apr 05, 2022)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins syndrome
Affected status: yes
Allele origin:
de novo
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Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues
Accession: SCV003035475.1
First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023 |
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Pathogenic
(Feb 14, 2023)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV003882800.2
First in ClinVar: Apr 15, 2023 Last updated: May 01, 2024 |
Comment:
The c.1876C>T (p.R626*) alteration, located in exon 18 (coding exon 17) of the TCF4 gene, consists of a C to T substitution at nucleotide position … (more)
The c.1876C>T (p.R626*) alteration, located in exon 18 (coding exon 17) of the TCF4 gene, consists of a C to T substitution at nucleotide position 1876. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 626. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in multiple individuals with clinical features of Pitt-Hopkins syndrome (Liu, 2018; Whalen, 2012). Based on the available evidence, this alteration is classified as pathogenic. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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protein truncation
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV002762860.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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A case of Pitt-hopkins Syndrome with de novo mutation in TCF4: Clinical features and treatment for epilepsy. | Liu Y | International journal of developmental neuroscience : the official journal of the International Society for Developmental Neuroscience | 2018 | PMID: 29604340 |
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 |
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 rs1131691735 ...
HelpRecord last updated May 01, 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.