NM_001083962.2(TCF4):c.1738C>T (p.Arg580Trp) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 17, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000387138.8

Allele description [Variation Report for NM_001083962.2(TCF4):c.1738C>T (p.Arg580Trp)]

NM_001083962.2(TCF4):c.1738C>T (p.Arg580Trp)

Gene:

TCF4:transcription factor 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q21.2

Genomic location:

Preferred name:

NM_001083962.2(TCF4):c.1738C>T (p.Arg580Trp)

HGVS:

NC_000018.10:g.55228988G>A
NG_011716.2:g.412006C>T
NM_001083962.1(TCF4):c.1738C>T
NM_001083962.2:c.1738C>TMANE SELECT
NM_001243226.3:c.2044C>T
NM_001243227.2:c.1666C>T
NM_001243228.2:c.1756C>T
NM_001243230.2:c.1717C>T
NM_001243231.2:c.1600C>T
NM_001243232.1:c.1525C>T
NM_001243233.2:c.1336C>T
NM_001243234.2:c.1258C>T
NM_001243235.2:c.1246C>T
NM_001243236.2:c.1246C>T
NM_001306207.1:c.1654C>T
NM_001306208.1:c.1513C>T
NM_001330604.3:c.1735C>T
NM_001330605.3:c.1348C>T
NM_001348211.2:c.1612C>T
NM_001348212.2:c.1336C>T
NM_001348213.2:c.1348C>T
NM_001348214.2:c.1243C>T
NM_001348215.2:c.1090C>T
NM_001348216.2:c.1258C>T
NM_001348217.1:c.1666C>T
NM_001348218.2:c.1666C>T
NM_001348219.2:c.1654C>T
NM_001348220.1:c.1651C>T
NM_001369567.1:c.1738C>T
NM_001369568.1:c.1738C>T
NM_001369569.1:c.1735C>T
NM_001369570.1:c.1735C>T
NM_001369571.1:c.1726C>T
NM_001369572.1:c.1726C>T
NM_001369573.1:c.1723C>T
NM_001369574.1:c.1723C>T
NM_001369575.1:c.1666C>T
NM_001369576.1:c.1663C>T
NM_001369577.1:c.1663C>T
NM_001369578.1:c.1663C>T
NM_001369579.1:c.1663C>T
NM_001369580.1:c.1663C>T
NM_001369581.1:c.1663C>T
NM_001369582.1:c.1654C>T
NM_001369583.1:c.1654C>T
NM_001369584.1:c.1651C>T
NM_001369585.1:c.1651C>T
NM_001369586.1:c.1669C>T
NM_003199.3:c.1726C>T
NP_001077431.1:p.Arg580Trp
NP_001230155.2:p.Arg682Trp
NP_001230156.1:p.Arg556Trp
NP_001230157.1:p.Arg586Trp
NP_001230159.1:p.Arg573Trp
NP_001230160.1:p.Arg534Trp
NP_001230161.1:p.Arg509Trp
NP_001230162.1:p.Arg446Trp
NP_001230163.1:p.Arg420Trp
NP_001230164.1:p.Arg416Trp
NP_001230165.1:p.Arg416Trp
NP_001293136.1:p.Arg552Trp
NP_001293137.1:p.Arg505Trp
NP_001317533.1:p.Arg579Trp
NP_001317534.1:p.Arg450Trp
NP_001335140.1:p.Arg538Trp
NP_001335141.1:p.Arg446Trp
NP_001335142.1:p.Arg450Trp
NP_001335143.1:p.Arg415Trp
NP_001335144.1:p.Arg364Trp
NP_001335145.1:p.Arg420Trp
NP_001335146.1:p.Arg556Trp
NP_001335147.1:p.Arg556Trp
NP_001335148.1:p.Arg552Trp
NP_001335149.1:p.Arg551Trp
NP_001356496.1:p.Arg580Trp
NP_001356497.1:p.Arg580Trp
NP_001356498.1:p.Arg579Trp
NP_001356499.1:p.Arg579Trp
NP_001356500.1:p.Arg576Trp
NP_001356501.1:p.Arg576Trp
NP_001356502.1:p.Arg575Trp
NP_001356503.1:p.Arg575Trp
NP_001356504.1:p.Arg556Trp
NP_001356505.1:p.Arg555Trp
NP_001356506.1:p.Arg555Trp
NP_001356507.1:p.Arg555Trp
NP_001356508.1:p.Arg555Trp
NP_001356509.1:p.Arg555Trp
NP_001356510.1:p.Arg555Trp
NP_001356511.1:p.Arg552Trp
NP_001356512.1:p.Arg552Trp
NP_001356513.1:p.Arg551Trp
NP_001356514.1:p.Arg551Trp
NP_001356515.1:p.Arg557Trp
NP_003190.1:p.Arg576Trp
NC_000018.9:g.52896219G>A
NM_001083962.1(TCF4):c.1738C>T
NM_001083962.1:c.1738C>T
NM_001243226.2:c.2044C>T
p.Arg580Trp

Protein change:

R364W; ARG576TRP

Links:

OMIM: 602272.0001; dbSNP: rs121909120

NCBI 1000 Genomes Browser:

rs121909120

Molecular consequence:

NM_001083962.2:c.1738C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243226.3:c.2044C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243227.2:c.1666C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243228.2:c.1756C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243230.2:c.1717C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243231.2:c.1600C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243232.1:c.1525C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243233.2:c.1336C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243234.2:c.1258C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243235.2:c.1246C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001243236.2:c.1246C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306207.1:c.1654C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001306208.1:c.1513C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330604.3:c.1735C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001330605.3:c.1348C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348211.2:c.1612C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348212.2:c.1336C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348213.2:c.1348C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348214.2:c.1243C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348215.2:c.1090C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348216.2:c.1258C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348217.1:c.1666C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348218.2:c.1666C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348219.2:c.1654C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001348220.1:c.1651C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369567.1:c.1738C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369568.1:c.1738C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369569.1:c.1735C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369570.1:c.1735C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369571.1:c.1726C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369572.1:c.1726C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369573.1:c.1723C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369574.1:c.1723C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369575.1:c.1666C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369576.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369577.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369578.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369579.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369580.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369581.1:c.1663C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369582.1:c.1654C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369583.1:c.1654C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369584.1:c.1651C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369585.1:c.1651C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369586.1:c.1669C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_003199.3:c.1726C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000329544	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 17, 2023)	germline	clinical testing	Citation Link,
SCV001430911	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 28, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV001447787	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000329544

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 17, 2023)

germline

clinical testing

Citation Link,

SCV001430911

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jul 28, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV001447787

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 23, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From GeneDx, SCV000329544.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

In vitro and in vivo functional studies indicate it alters protein localization and affects homo- and heterodimer formation, thereby inhibiting protein-protein interactions (Sepp et al., 2012; Forrest et al,. 2012); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22460224, 29318938, 22777675, 17436254, 18781613, 26621827, 17436255, 16531728, 29655203, 31130284, 32369273, 33624935, 31785789, 35599849, 35719373)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center, SCV001430911.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

PS2, PS3, PS4, PM2

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447787.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	1	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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