ClinVar Genomic variation as it relates to human health
NM_001083962.2(TCF4):c.990G>A (p.Ser330=)
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.990G>A (p.Ser330=)
Variation ID: 160092 Accession: VCV000160092.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.2 18: 55261466 (GRCh38) [ NCBI UCSC ] 18: 52928697 (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 Nov 23, 2014 May 12, 2024 Feb 23, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001083962.2:c.990G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001077431.1:p.Ser330= synonymous NM_001243226.3:c.1296G>A NP_001230155.2:p.Ser432= synonymous NM_001243227.2:c.918G>A NP_001230156.1:p.Ser306= synonymous NM_001243228.2:c.1008G>A NP_001230157.1:p.Ser336= synonymous NM_001243230.2:c.984G>A NP_001230159.1:p.Ser328= synonymous NM_001243231.2:c.864G>A NP_001230160.1:p.Ser288= synonymous NM_001243232.1:c.777G>A NP_001230161.1:p.Ser259= synonymous NM_001243233.2:c.600G>A NP_001230162.1:p.Ser200= synonymous NM_001243234.2:c.510G>A NP_001230163.1:p.Ser170= synonymous NM_001243235.2:c.510G>A NP_001230164.1:p.Ser170= synonymous NM_001243236.2:c.510G>A NP_001230165.1:p.Ser170= synonymous NM_001306207.1:c.918G>A NP_001293136.1:p.Ser306= synonymous NM_001306208.1:c.777G>A NP_001293137.1:p.Ser259= synonymous NM_001330604.3:c.990G>A NP_001317533.1:p.Ser330= synonymous NM_001330605.3:c.600G>A NP_001317534.1:p.Ser200= synonymous NM_001348211.2:c.864G>A NP_001335140.1:p.Ser288= synonymous NM_001348212.2:c.600G>A NP_001335141.1:p.Ser200= synonymous NM_001348213.2:c.600G>A NP_001335142.1:p.Ser200= synonymous NM_001348214.2:c.510G>A NP_001335143.1:p.Ser170= synonymous NM_001348215.2:c.342G>A NP_001335144.1:p.Ser114= synonymous NM_001348216.2:c.510G>A NP_001335145.1:p.Ser170= synonymous NM_001348217.1:c.918G>A NP_001335146.1:p.Ser306= synonymous NM_001348218.2:c.918G>A NP_001335147.1:p.Ser306= synonymous NM_001348219.2:c.918G>A NP_001335148.1:p.Ser306= synonymous NM_001348220.1:c.915G>A NP_001335149.1:p.Ser305= synonymous NM_001369567.1:c.990G>A NP_001356496.1:p.Ser330= synonymous NM_001369568.1:c.990G>A NP_001356497.1:p.Ser330= synonymous NM_001369569.1:c.987G>A NP_001356498.1:p.Ser329= synonymous NM_001369570.1:c.987G>A NP_001356499.1:p.Ser329= synonymous NM_001369571.1:c.990G>A NP_001356500.1:p.Ser330= synonymous NM_001369572.1:c.990G>A NP_001356501.1:p.Ser330= synonymous NM_001369573.1:c.987G>A NP_001356502.1:p.Ser329= synonymous NM_001369574.1:c.990G>A NP_001356503.1:p.Ser330= synonymous NM_001369575.1:c.918G>A NP_001356504.1:p.Ser306= synonymous NM_001369576.1:c.915G>A NP_001356505.1:p.Ser305= synonymous NM_001369577.1:c.918G>A NP_001356506.1:p.Ser306= synonymous NM_001369578.1:c.915G>A NP_001356507.1:p.Ser305= synonymous NM_001369579.1:c.918G>A NP_001356508.1:p.Ser306= synonymous NM_001369580.1:c.918G>A NP_001356509.1:p.Ser306= synonymous NM_001369581.1:c.915G>A NP_001356510.1:p.Ser305= synonymous NM_001369582.1:c.918G>A NP_001356511.1:p.Ser306= synonymous NM_001369583.1:c.918G>A NP_001356512.1:p.Ser306= synonymous NM_001369584.1:c.915G>A NP_001356513.1:p.Ser305= synonymous NM_001369585.1:c.915G>A NP_001356514.1:p.Ser305= synonymous NM_001369586.1:c.918G>A NP_001356515.1:p.Ser306= synonymous NM_003199.3:c.990G>A NP_003190.1:p.Ser330= synonymous NC_000018.10:g.55261466C>T NC_000018.9:g.52928697C>T NG_011716.2:g.379528G>A - Protein change
- Other names
- NM_001083962.2(TCF4):c.990G>A
- Canonical SPDI
- NC_000018.10:55261465:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- Variation affecting splicing function of RNA Variation Ontology [VariO:0397]
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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
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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
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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 (4) |
reviewed by expert panel
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Feb 23, 2024 | RCV000147730.13 | |
Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 19, 2023 | RCV000521305.12 |
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
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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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Pathogenic
(Feb 23, 2024)
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reviewed by expert panel
Method: curation
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Pitt-Hopkins syndrome
(Autosomal dominant inheritance)
Affected status: unknown
Allele origin:
germline
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ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel
Accession: SCV001712000.2
First in ClinVar: Jun 08, 2021 Last updated: Apr 06, 2024 |
Comment:
The p.Ser330= variant in TCF4 is absent from gnomAD v4 (PM2_supporting). Splice prediction analysis using multiple computational tools suggests an impact to splicing (PP3). The … (more)
The p.Ser330= variant in TCF4 is absent from gnomAD v4 (PM2_supporting). Splice prediction analysis using multiple computational tools suggests an impact to splicing (PP3). The p.Ser330= variant has been observed in at least 2 individuals with intellectual disability/autism (PMIDs: 29695756, 25693842) (PS4_supporting). The p.Ser330= variant in TCF4 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with intellectual disability (PMID: 25693842, internal database -Invitae) (PM6). The p.Ser330= variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in at least 3 individuals with intellectual disability/autism (PMIDs: 29695756, 29158550, 31785789, 1981491, 33767182, internal database - Invitae) (PS2_very strong). In summary, the p.Ser330= variant in TCF4 is classified as pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM2_supporting, PP3, PS4_supporting, PM6, PS2_very strong). (less)
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Likely pathogenic
(Apr 01, 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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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004010982.7
First in ClinVar: Jul 16, 2023 Last updated: May 12, 2024 |
Comment:
TCF4: PS2, PM2:Supporting, PP3, PS4:Supporting
Number of individuals with the variant: 1
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Likely pathogenic
(Feb 20, 2014)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins syndrome
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
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Genetic Services Laboratory, University of Chicago
Accession: SCV000195195.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
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Pathogenic
(Aug 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins syndrome
(Sporadic)
Affected status: yes
Allele origin:
de novo
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Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV000586709.1
First in ClinVar: Nov 23, 2014 Last updated: Nov 23, 2014 |
Comment:
De novo variant at the last nucleotide position in gxon 13 of the TCF4 gene in a patient with hypotonia and developmental delay. This Variant … (more)
De novo variant at the last nucleotide position in gxon 13 of the TCF4 gene in a patient with hypotonia and developmental delay. This Variant has been previously reported as de novo (PMID22495309) in a patient with ID. In house splicing assays showed aberrant splicing. The variant is thus scored as pathogenic (ACMG class 5). (less)
Clinical Features:
Intellectual disability (present)
Sex: female
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Pathogenic
(Aug 28, 2022)
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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: SCV000616931.3
First in ClinVar: Dec 19, 2017 Last updated: Mar 04, 2023 |
Comment:
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the … (more)
Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25693842, 29695756, 33767182, 28191890, 22495309, 25780760, 32579932, 27694994, 31785789, 29158550, 32369273, 31069529, 31981491) (less)
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Pathogenic
(Feb 16, 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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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV003844864.1
First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023 |
Comment:
Variant summary: TCF4 c.990G>A (p.Ser330Ser) alters the non-conserved last nucleotide of exon 12 and therefore could affect mRNA splicing, leading to a significantly altered protein … (more)
Variant summary: TCF4 c.990G>A (p.Ser330Ser) alters the non-conserved last nucleotide of exon 12 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. One submitter via Clinvar stated that an in house splicing assay showed aberrant splicing, however did not provide supporting data (Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universitt Erlangen-Nrnberg). The variant was absent in 250940 control chromosomes. c.990G>A has been reported in the literature in individuals affected with Pitt-Hopkins Syndrome, autism spectrum disorder, intellectual disabilities, and neurodevelopmental disorders, including multiple affected individuals in which the variant was de novo (e.g., Geoffrey_2015, Tan_2016, Popp_2017, Mary_2018, Turner_2019, Satterstrom_2020, Martinez-Granero_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported in the literature. Three ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
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Pathogenic
(May 19, 2023)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV004026398.1
First in ClinVar: Aug 19, 2023 Last updated: Aug 19, 2023 |
Comment:
PS4, PP3, PM2_SUP
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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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Variation affecting splicing function of RNA
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Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg
Accession: SCV000586709.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Comparison of the diagnostic yield of aCGH and genome-wide sequencing across different neurodevelopmental disorders. | Martinez-Granero F | NPJ genomic medicine | 2021 | PMID: 33767182 |
Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism. | Satterstrom FK | Cell | 2020 | PMID: 31981491 |
Sex-Based Analysis of De Novo Variants in Neurodevelopmental Disorders. | Turner TN | American journal of human genetics | 2019 | PMID: 31785789 |
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 |
Exome Pool-Seq in neurodevelopmental disorders. | Popp B | European journal of human genetics : EJHG | 2017 | PMID: 29158550 |
Characterization of patients referred for non-specific intellectual disability testing: the importance of autosomal genes for diagnosis. | Tan CA | Clinical genetics | 2016 | PMID: 25693842 |
VaRank: a simple and powerful tool for ranking genetic variants. | Geoffroy V | PeerJ | 2015 | PMID: 25780760 |
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/919996d2-6306-4345-9cff-1b4b6bd7694d | - | - | - | - |
Text-mined citations for rs587784469 ...
HelpRecord last updated May 12, 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.