VCV000581714.14 - ClinVar

NM_001083962.2(TCF4):c.1841C>T (p.Ala614Val)

Germline

Classification

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.

(6)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001083962.2(TCF4):c.1841C>T (p.Ala614Val)

Variation ID: 581714 Accession: VCV000581714.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 18q21.2 18: 55228885 (GRCh38) [ NCBI UCSC ] 18: 52896116 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 10, 2018	Sep 16, 2024	Jul 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001083962.2:c.1841C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001077431.1:p.Ala614Val	missense
NM_001243226.3:c.2147C>T	NP_001230155.2:p.Ala716Val	missense
NM_001243227.2:c.1769C>T	NP_001230156.1:p.Ala590Val	missense
NM_001243228.2:c.1859C>T	NP_001230157.1:p.Ala620Val	missense
NM_001243230.2:c.1820C>T	NP_001230159.1:p.Ala607Val	missense
NM_001243231.2:c.1703C>T	NP_001230160.1:p.Ala568Val	missense
NM_001243232.1:c.1628C>T	NP_001230161.1:p.Ala543Val	missense
NM_001243233.2:c.1439C>T	NP_001230162.1:p.Ala480Val	missense
NM_001243234.2:c.1361C>T	NP_001230163.1:p.Ala454Val	missense
NM_001243235.2:c.1349C>T	NP_001230164.1:p.Ala450Val	missense
NM_001243236.2:c.1349C>T	NP_001230165.1:p.Ala450Val	missense
NM_001306207.1:c.1757C>T	NP_001293136.1:p.Ala586Val	missense
NM_001306208.1:c.1616C>T	NP_001293137.1:p.Ala539Val	missense
NM_001330604.3:c.1838C>T	NP_001317533.1:p.Ala613Val	missense
NM_001330605.3:c.1451C>T	NP_001317534.1:p.Ala484Val	missense
NM_001348211.2:c.1715C>T	NP_001335140.1:p.Ala572Val	missense
NM_001348212.2:c.1439C>T	NP_001335141.1:p.Ala480Val	missense
NM_001348213.2:c.1451C>T	NP_001335142.1:p.Ala484Val	missense
NM_001348214.2:c.1346C>T	NP_001335143.1:p.Ala449Val	missense
NM_001348215.2:c.1193C>T	NP_001335144.1:p.Ala398Val	missense
NM_001348216.2:c.1361C>T	NP_001335145.1:p.Ala454Val	missense
NM_001348217.1:c.1769C>T	NP_001335146.1:p.Ala590Val	missense
NM_001348218.2:c.1769C>T	NP_001335147.1:p.Ala590Val	missense
NM_001348219.2:c.1757C>T	NP_001335148.1:p.Ala586Val	missense
NM_001348220.1:c.1754C>T	NP_001335149.1:p.Ala585Val	missense
NM_001369567.1:c.1841C>T	NP_001356496.1:p.Ala614Val	missense
NM_001369568.1:c.1841C>T	NP_001356497.1:p.Ala614Val	missense
NM_001369569.1:c.1838C>T	NP_001356498.1:p.Ala613Val	missense
NM_001369570.1:c.1838C>T	NP_001356499.1:p.Ala613Val	missense
NM_001369571.1:c.1829C>T	NP_001356500.1:p.Ala610Val	missense
NM_001369572.1:c.1829C>T	NP_001356501.1:p.Ala610Val	missense
NM_001369573.1:c.1826C>T	NP_001356502.1:p.Ala609Val	missense
NM_001369574.1:c.1826C>T	NP_001356503.1:p.Ala609Val	missense
NM_001369575.1:c.1769C>T	NP_001356504.1:p.Ala590Val	missense
NM_001369576.1:c.1766C>T	NP_001356505.1:p.Ala589Val	missense
NM_001369577.1:c.1766C>T	NP_001356506.1:p.Ala589Val	missense
NM_001369578.1:c.1766C>T	NP_001356507.1:p.Ala589Val	missense
NM_001369579.1:c.1766C>T	NP_001356508.1:p.Ala589Val	missense
NM_001369580.1:c.1766C>T	NP_001356509.1:p.Ala589Val	missense
NM_001369581.1:c.1766C>T	NP_001356510.1:p.Ala589Val	missense
NM_001369582.1:c.1757C>T	NP_001356511.1:p.Ala586Val	missense
NM_001369583.1:c.1757C>T	NP_001356512.1:p.Ala586Val	missense
NM_001369584.1:c.1754C>T	NP_001356513.1:p.Ala585Val	missense
NM_001369585.1:c.1754C>T	NP_001356514.1:p.Ala585Val	missense
NM_001369586.1:c.1772C>T	NP_001356515.1:p.Ala591Val	missense
NM_003199.3:c.1829C>T	NP_003190.1:p.Ala610Val	missense
NC_000018.10:g.55228885G>A
NC_000018.9:g.52896116G>A
NG_011716.2:g.412109C>T

... more HGVS ... less HGVS

Protein change

A614V, A398V, A449V, A450V, A454V, A480V, A539V, A543V, A585V, A590V, A607V, A609V, A620V, A716V, A484V, A572V, A591V, A613V, A568V, A586V, A589V, A610V

Other names

Canonical SPDI

NC_000018.10:55228884:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

dbSNP: rs1568303352 VarSome

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
Gene	OMIM	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	993	1220

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.
Pitt-Hopkins syndrome	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Dec 12, 2023	RCV000705624.12
not provided	Pathogenic (4)	criteria provided, single submitter	Jul 11, 2024	RCV001561077.5

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.
Pathogenic (Dec 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Pitt-Hopkins syndrome (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV004175740.1 First in ClinVar: Dec 17, 2023 Last updated: Dec 17, 2023	Clinical Features: Microcephaly (present) , Posteriorly rotated ears (present) , Motor stereotypies (present) , Delayed speech and language development (present) , Hypotonia (present) , Global developmental delay … (more) Microcephaly (present) , Posteriorly rotated ears (present) , Motor stereotypies (present) , Delayed speech and language development (present) , Hypotonia (present) , Global developmental delay (present) , Gait ataxia (present) (less)
Pathogenic (Aug 28, 2019)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Pitt-Hopkins syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000834630.6 First in ClinVar: Oct 10, 2018 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 28492532‚ 22460224‚ 22777675‚ 26621827‚ 19235238‚ 29695756 Comment: Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this … (more) Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect TCF4 protein function (PMID: 22460224, 22777675, 26621827). This variant has been observed to be de novo in individuals affected with Pitt-Hopkins syndrome (PMID: 19235238, 29695756). This variant is also known as c.1823C>T (p.Ala610Val) in the literature. ClinVar contains an entry for this variant (Variation ID: 581714). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 614 of the TCF4 protein (p.Ala614Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. (less)
Pathogenic (Jul 11, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001783609.2 First in ClinVar: Aug 14, 2021 Last updated: Sep 16, 2024	Comment: Published in vitro functional studies demonstrate a damaging effect with elevated degradation of the protein through the proteasome pathway, impaired DNA binding, and abolished homodimerization … (more) Published in vitro functional studies demonstrate a damaging effect with elevated degradation of the protein through the proteasome pathway, impaired DNA binding, and abolished homodimerization ability (PMID: 22460224, 26621827); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22777675, 29695756, 26621827, 22045651, 31666615, 22460224, 19235238, 32959227, 35982160, 33057194, 35982159) (less)
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927139.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001952406.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Pathogenic (Apr 14, 2021)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: de novo	Molecular Genetics laboratory, Necker Hospital Accession: SCV004031383.1 First in ClinVar: Sep 03, 2023 Last updated: Sep 03, 2023	Clinical Features: Intellectual disability (present)

Comment:

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect TCF4 protein function (PMID: 22460224, 22777675, 26621827). This variant has been observed to be de novo in individuals affected with Pitt-Hopkins syndrome (PMID: 19235238, 29695756). This variant is also known as c.1823C>T (p.Ala610Val) in the literature. ClinVar contains an entry for this variant (Variation ID: 581714). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with valine at codon 614 of the TCF4 protein (p.Ala614Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine.

Comment:

Published in vitro functional studies demonstrate a damaging effect with elevated degradation of the protein through the proteasome pathway, impaired DNA binding, and abolished homodimerization ability (PMID: 22460224, 26621827); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22777675, 29695756, 26621827, 22045651, 31666615, 22460224, 19235238, 32959227, 35982160, 33057194, 35982159)

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
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
Introducing Pitt-Hopkins syndrome-associated mutations of TCF4 to Drosophila daughterless.	Tamberg L	Biology open	2015	PMID: 26621827
Functional analysis of TCF4 missense mutations that cause Pitt-Hopkins syndrome.	Forrest M	Human mutation	2012	PMID: 22777675
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
Mutational, functional, and expression studies of the TCF4 gene in Pitt-Hopkins syndrome.	de Pontual L	Human mutation	2009	PMID: 19235238

Text-mined citations for rs1568303352 ...

These 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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_001083962.2(TCF4):c.1841C>T (p.Ala614Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs1568303352 ...