This 6 year old male with global developmental delays, hypotonia, cryptorchidism, and large stature was found to carry a missense variant in the TCF4 gene. At the date of report, he had no history of seizure activity or hypervenitlation, but he was noted to have dysmorphic features, including mild brachycephaly, narrow palpebral fissures, overfolded helices and small, pointed tragi, a single transverse palmar crease on the right hand, and a shortened transverse palmar crease on the left hand. The p.Val617Phe variant is absent from population databases and has not been reported in other individuals with Pitt-Hopkins syndrome, to our knowledge. Computational models predict the variant to be probably damaging. A variant at codon 614 has been reported previously in an individual with Pitt-Hopkins, which supports the functional importance of this region.
ClinVar Genomic variation as it relates to human health
NM_001083962.2(TCF4):c.1849G>T (p.Val617Phe)
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.
(2)
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.
Likely pathogenic
2
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.1849G>T (p.Val617Phe)
Variation ID: 560273 Accession: VCV000560273.3
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 18q21.2 18: 55228877 (GRCh38) [ NCBI UCSC ] 18: 52896108 (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 Sep 7, 2018 Dec 11, 2022 Feb 17, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001083962.2:c.1849G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001077431.1:p.Val617Phe missense NM_001243226.3:c.2155G>T NP_001230155.2:p.Val719Phe missense NM_001243227.2:c.1777G>T NP_001230156.1:p.Val593Phe missense NM_001243228.2:c.1867G>T NP_001230157.1:p.Val623Phe missense NM_001243230.2:c.1828G>T NP_001230159.1:p.Val610Phe missense NM_001243231.2:c.1711G>T NP_001230160.1:p.Val571Phe missense NM_001243232.1:c.1636G>T NP_001230161.1:p.Val546Phe missense NM_001243233.2:c.1447G>T NP_001230162.1:p.Val483Phe missense NM_001243234.2:c.1369G>T NP_001230163.1:p.Val457Phe missense NM_001243235.2:c.1357G>T NP_001230164.1:p.Val453Phe missense NM_001243236.2:c.1357G>T NP_001230165.1:p.Val453Phe missense NM_001306207.1:c.1765G>T NP_001293136.1:p.Val589Phe missense NM_001306208.1:c.1624G>T NP_001293137.1:p.Val542Phe missense NM_001330604.3:c.1846G>T NP_001317533.1:p.Val616Phe missense NM_001330605.3:c.1459G>T NP_001317534.1:p.Val487Phe missense NM_001348211.2:c.1723G>T NP_001335140.1:p.Val575Phe missense NM_001348212.2:c.1447G>T NP_001335141.1:p.Val483Phe missense NM_001348213.2:c.1459G>T NP_001335142.1:p.Val487Phe missense NM_001348214.2:c.1354G>T NP_001335143.1:p.Val452Phe missense NM_001348215.2:c.1201G>T NP_001335144.1:p.Val401Phe missense NM_001348216.2:c.1369G>T NP_001335145.1:p.Val457Phe missense NM_001348217.1:c.1777G>T NP_001335146.1:p.Val593Phe missense NM_001348218.2:c.1777G>T NP_001335147.1:p.Val593Phe missense NM_001348219.2:c.1765G>T NP_001335148.1:p.Val589Phe missense NM_001348220.1:c.1762G>T NP_001335149.1:p.Val588Phe missense NM_001369567.1:c.1849G>T NP_001356496.1:p.Val617Phe missense NM_001369568.1:c.1849G>T NP_001356497.1:p.Val617Phe missense NM_001369569.1:c.1846G>T NP_001356498.1:p.Val616Phe missense NM_001369570.1:c.1846G>T NP_001356499.1:p.Val616Phe missense NM_001369571.1:c.1837G>T NP_001356500.1:p.Val613Phe missense NM_001369572.1:c.1837G>T NP_001356501.1:p.Val613Phe missense NM_001369573.1:c.1834G>T NP_001356502.1:p.Val612Phe missense NM_001369574.1:c.1834G>T NP_001356503.1:p.Val612Phe missense NM_001369575.1:c.1777G>T NP_001356504.1:p.Val593Phe missense NM_001369576.1:c.1774G>T NP_001356505.1:p.Val592Phe missense NM_001369577.1:c.1774G>T NP_001356506.1:p.Val592Phe missense NM_001369578.1:c.1774G>T NP_001356507.1:p.Val592Phe missense NM_001369579.1:c.1774G>T NP_001356508.1:p.Val592Phe missense NM_001369580.1:c.1774G>T NP_001356509.1:p.Val592Phe missense NM_001369581.1:c.1774G>T NP_001356510.1:p.Val592Phe missense NM_001369582.1:c.1765G>T NP_001356511.1:p.Val589Phe missense NM_001369583.1:c.1765G>T NP_001356512.1:p.Val589Phe missense NM_001369584.1:c.1762G>T NP_001356513.1:p.Val588Phe missense NM_001369585.1:c.1762G>T NP_001356514.1:p.Val588Phe missense NM_001369586.1:c.1780G>T NP_001356515.1:p.Val594Phe missense NM_003199.3:c.1837G>T NP_003190.1:p.Val613Phe missense NC_000018.10:g.55228877C>A NC_000018.9:g.52896108C>A NG_011716.2:g.412117G>T - Protein change
- V617F, V453F, V546F, V613F, V623F, V571F, V588F, V589F, V592F, V593F, V401F, V452F, V487F, V610F, V616F, V719F, V457F, V483F, V542F, V575F, V594F, V612F
- Other names
- -
- Canonical SPDI
- NC_000018.10:55228876:C: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.
- -
- 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. |
|||
| TCF4 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
988 | 1215 | |
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. |
|---|---|---|---|---|
| Likely pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Feb 17, 2022 | RCV000678346.4 |
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
(Feb 17, 2022)
|
criteria provided, single submitter
Method: clinical testing
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Pitt-Hopkins syndrome
Affected status: yes
Allele origin:
germline
|
MGZ Medical Genetics Center
Accession: SCV002579827.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022
Comment:
ACMG criteria applied: PM1, PM5, PM2_SUP, PP3
|
Number of individuals with the variant: 1
Sex: male
|
|
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Likely pathogenic
(Mar 29, 2017)
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criteria provided, single submitter
Method: provider interpretation, clinical testing
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Pitt-Hopkins syndrome
Affected status: yes
Allele origin:
de novo
|
Geisinger Autism and Developmental Medicine Institute, Geisinger Health System
Accession: SCV000804410.2
First in ClinVar: Sep 07, 2018 Last updated: Dec 11, 2022 |
Comment:
This 6 year old male with global developmental delays, hypotonia, cryptorchidism, and large stature was found to carry a missense variant in the TCF4 gene. … (more)
This 6 year old male with global developmental delays, hypotonia, cryptorchidism, and large stature was found to carry a missense variant in the TCF4 gene. At the date of report, he had no history of seizure activity or hypervenitlation, but he was noted to have dysmorphic features, including mild brachycephaly, narrow palpebral fissures, overfolded helices and small, pointed tragi, a single transverse palmar crease on the right hand, and a shortened transverse palmar crease on the left hand. The p.Val617Phe variant is absent from population databases and has not been reported in other individuals with Pitt-Hopkins syndrome, to our knowledge. Computational models predict the variant to be probably damaging. A variant at codon 614 has been reported previously in an individual with Pitt-Hopkins, which supports the functional importance of this region. (less)
Observation 1:
Clinical Features:
Global developmental delay (present) , Muscular hypotonia (present) , Tall stature (present) , Cryptorchidism (present)
Age: 0-9 years
Sex: male
Secondary finding: no
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-03-29
Testing laboratory interpretation: Likely pathogenic
Observation 2:
Number of individuals with the variant: 1
Clinical Features:
Global developmental delay (present) , Muscular hypotonia (present) , Tall stature (present) , Cryptorchidism (present)
Age: 0-9 years
Sex: male
Testing laboratory: GeneDx
Date variant was reported to submitter: 2017-03-29
Testing laboratory interpretation: Likely pathogenic
|
Comment:
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:
This 6 year old male with global developmental delays, hypotonia, cryptorchidism, and large stature was found to carry a missense variant in the TCF4 gene. At the date of report, he had no history of seizure activity or hypervenitlation, but he was noted to have dysmorphic features, including mild brachycephaly, narrow palpebral fissures, overfolded helices and small, pointed tragi, a single transverse palmar crease on the right hand, and a shortened transverse palmar crease on the left hand. The p.Val617Phe variant is absent from population databases and has not been reported in other individuals with Pitt-Hopkins syndrome, to our knowledge. Computational models predict the variant to be probably damaging. A variant at codon 614 has been reported previously in an individual with Pitt-Hopkins, which supports the functional importance of this region.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. | Stenson PD | Human genetics | 2014 | PMID: 24077912 |
| 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 |
Text-mined citations for rs1568303086 ...
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 May 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.