Evidence Repository
The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC computed assertion could be determined for this classification!

Variant: NM_001083962.2(TCF4):c.1741G>T (p.Val581Phe)

CA272702

160079 (ClinVar)

Gene: TCF4 (HGNC:6925)
Condition: Pitt-Hopkins syndrome (MONDO:0012589)
Inheritance Mode: Autosomal dominant inheritance
UUID: 79c2b5b6-3037-44fa-ae71-0b48cd373e7a
Approved on: 2026-07-01
Published on: 2026-10-16

HGVS expressions

NM_001083962.2:c.1741G>T
NM_001083962.2(TCF4):c.1741G>T (p.Val581Phe)
NC_000018.10:g.55228985C>A
CM000680.2:g.55228985C>A
NC_000018.9:g.52896216C>A
CM000680.1:g.52896216C>A
NC_000018.8:g.51047214C>A
NG_011716.1:g.364645G>T
NG_011716.2:g.412009G>T
ENST00000354452.8:c.1741G>T
ENST00000635822.2:c.1621G>T
ENST00000635990.2:n.1421G>T
ENST00000636400.2:c.1669G>T
ENST00000636751.2:c.*1449G>T
ENST00000636822.2:c.1351G>T
ENST00000637115.2:c.*1619G>T
ENST00000637169.2:c.1093G>T
ENST00000637239.2:n.1796G>T
ENST00000637250.2:n.1435G>T
ENST00000637923.2:c.1339G>T
ENST00000638154.3:c.1768G>T
ENST00000643689.1:c.1351G>T
ENST00000674764.1:c.*1352G>T
ENST00000675707.1:c.1351G>T
ENST00000354452.7:c.1741G>T
ENST00000356073.8:c.1729G>T
ENST00000398339.5:c.2047G>T
ENST00000457482.7:c.1261G>T
ENST00000537578.5:c.1669G>T
ENST00000537856.7:c.1339G>T
ENST00000540999.5:c.1657G>T
ENST00000543082.5:c.1603G>T
ENST00000544241.6:c.1528G>T
ENST00000561831.7:c.1249G>T
ENST00000561992.5:c.1339G>T
ENST00000562680.5:n.5264G>T
ENST00000564228.5:c.1516G>T
ENST00000564403.6:c.1759G>T
ENST00000564999.5:c.1729G>T
ENST00000565018.6:c.1477G>T
ENST00000566279.5:c.1561G>T
ENST00000566286.5:c.1720G>T
ENST00000567880.5:c.1549G>T
ENST00000568673.5:c.1669G>T
ENST00000568740.5:c.1654G>T
ENST00000570177.6:c.1339G>T
ENST00000570287.6:c.1249G>T
ENST00000616053.4:c.1477G>T
ENST00000626466.1:n.764G>T
ENST00000626584.2:c.1081G>T
ENST00000629387.2:c.1741G>T
NM_001083962.1:c.1741G>T
NM_001243226.2:c.2047G>T
NM_001243227.1:c.1669G>T
NM_001243228.1:c.1759G>T
NM_001243230.1:c.1720G>T
NM_001243231.1:c.1603G>T
NM_001243232.1:c.1528G>T
NM_001243233.1:c.1339G>T
NM_001243234.1:c.1261G>T
NM_001243235.1:c.1249G>T
NM_001243236.1:c.1249G>T
NM_001306207.1:c.1657G>T
NM_001306208.1:c.1516G>T
NM_003199.2:c.1729G>T
NM_001330604.2:c.1738G>T
NM_001330605.2:c.1351G>T
NM_001348211.1:c.1615G>T
NM_001348212.1:c.1339G>T
NM_001348213.1:c.1351G>T
NM_001348214.1:c.1246G>T
NM_001348215.1:c.1093G>T
NM_001348216.1:c.1261G>T
NM_001348217.1:c.1669G>T
NM_001348218.1:c.1669G>T
NM_001348219.1:c.1657G>T
NM_001348220.1:c.1654G>T
NM_001243226.3:c.2047G>T
NM_001243227.2:c.1669G>T
NM_001243228.2:c.1759G>T
NM_001243231.2:c.1603G>T
NM_001243233.2:c.1339G>T
NM_001243234.2:c.1261G>T
NM_001243235.2:c.1249G>T
NM_001243236.2:c.1249G>T
NM_001330604.3:c.1738G>T
NM_001330605.3:c.1351G>T
NM_001348211.2:c.1615G>T
NM_001348212.2:c.1339G>T
NM_001348213.2:c.1351G>T
NM_001348214.2:c.1246G>T
NM_001348215.2:c.1093G>T
NM_001348216.2:c.1261G>T
NM_001348218.2:c.1669G>T
NM_001348219.2:c.1657G>T
NM_001369567.1:c.1741G>T
NM_001369568.1:c.1741G>T
NM_001369569.1:c.1738G>T
NM_001369570.1:c.1738G>T
NM_001369571.1:c.1729G>T
NM_001369572.1:c.1729G>T
NM_001369573.1:c.1726G>T
NM_001369574.1:c.1726G>T
NM_001369575.1:c.1669G>T
NM_001369576.1:c.1666G>T
NM_001369577.1:c.1666G>T
NM_001369578.1:c.1666G>T
NM_001369579.1:c.1666G>T
NM_001369580.1:c.1666G>T
NM_001369581.1:c.1666G>T
NM_001369582.1:c.1657G>T
NM_001369583.1:c.1657G>T
NM_001369584.1:c.1654G>T
NM_001369585.1:c.1654G>T
NM_001369586.1:c.1672G>T
NM_003199.3:c.1729G>T
NM_001243230.2:c.1720G>T
More

Likely Pathogenic

Met criteria codes 5
PM2_Supporting PP3 PM1 PM6 PS4_Supporting

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specification: ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TCF4 Version 6.0

Criteria Specification Approval History
Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The p.Val581Phe variant in TCF4 is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651) (PM1). This variant is absent from gnomAD (PM2_supporting). The p.Val581Phe variant in TCF4 occurs in the de novo state (biological parentage unconfirmed) in an individual with delays, hypotonia, not walking, dysmorphic features (University of Chicago internal database) (PM6). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Val581Phe variant in TCF4 has been observed in at least 2 individuals with neurodevelopmental phenotype (University of Chicago internal database, Labcorp Genetics (formerly Invitae) internal database) (PS4_supporting). In summary, the p.Val581Phe variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM1, PM2_supporting, PM6, PP3, PS4_supporting). (TCF4 Specifications v6.0.0; curation approved on 7/1/2026.)
Met criteria codes
PM2_Supporting
The p.Val581Phe variant in TCF4 is absent from gnomAD.
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own.
PM1
This variant is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651).
PM6
The p.Val581Phe variant in TCF4 occurs in the de novo state (biological parentage unconfirmed) in an individual with delays, hypotonia, not walking, dysmorphic features (University of Chicago internal database).
PS4_Supporting
The p.Val581Phe variant in TCF4 has been observed in at least 2 individuals with neurodevelopmental phenotype (University of Chicago internal database, Labcorp Genetics (formerly Invitae) internal database).
Curation History
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