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

CA272702

160079 (ClinVar)

Gene: TCF4
Condition: Pitt-Hopkins syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 79c2b5b6-3037-44fa-ae71-0b48cd373e7a
Approved on: 2022-02-18
Published on: 2022-06-30

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:n.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:n.1516G>T
ENST00000564403.6:c.1759G>T
ENST00000564999.5:c.1729G>T
ENST00000565018.6:c.1477G>T
ENST00000566279.5:c.1561G>T
ENST00000566286.5:n.1720G>T
ENST00000567880.5:n.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
PP3 PM1 PM6 PM2_Supporting PS4_Supporting

Evidence Links 0

Expert Panel

Criteria Specification Information

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, 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).
Met criteria codes
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).
PM2_Supporting
The p.Val581Phe variant in TCF4 is absent from gnomAD.
PS4_Supporting
The p.Val581Phe variant in TCF4 has been observed in at least 2 individuals with neurodevelopmental phenotype (University of Chicago internal database, Invitae internal database).
Curation History
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