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Variant: NM_001083962.2(TCF4):c.1744C>T (p.Arg582Cys)

CA402528894

1003911 (ClinVar)

Gene: TCF4
Condition: Pitt-Hopkins syndrome
Inheritance Mode: Autosomal dominant inheritance
UUID: fde6ec4c-57cf-47cc-959d-b6b4f69a46a6
Approved on: 2023-08-23
Published on: 2023-09-15

HGVS expressions

NM_001083962.2:c.1744C>T
NM_001083962.2(TCF4):c.1744C>T (p.Arg582Cys)
NC_000018.10:g.55228982G>A
CM000680.2:g.55228982G>A
NC_000018.9:g.52896213G>A
CM000680.1:g.52896213G>A
NC_000018.8:g.51047211G>A
NG_011716.1:g.364648C>T
NG_011716.2:g.412012C>T
ENST00000354452.8:c.1744C>T
ENST00000635822.2:c.1624C>T
ENST00000635990.2:n.1424C>T
ENST00000636400.2:c.1672C>T
ENST00000636751.2:c.*1452C>T
ENST00000636822.2:c.1354C>T
ENST00000637115.2:c.*1622C>T
ENST00000637169.2:c.1096C>T
ENST00000637239.2:n.1799C>T
ENST00000637250.2:n.1438C>T
ENST00000637923.2:c.1342C>T
ENST00000638154.3:c.1771C>T
ENST00000643689.1:c.1354C>T
ENST00000674764.1:c.*1355C>T
ENST00000675707.1:c.1354C>T
ENST00000354452.7:c.1744C>T
ENST00000356073.8:c.1732C>T
ENST00000398339.5:c.2050C>T
ENST00000457482.7:c.1264C>T
ENST00000537578.5:c.1672C>T
ENST00000537856.7:c.1342C>T
ENST00000540999.5:c.1660C>T
ENST00000543082.5:c.1606C>T
ENST00000544241.6:c.1531C>T
ENST00000561831.7:c.1252C>T
ENST00000561992.5:c.1342C>T
ENST00000562680.5:n.5267C>T
ENST00000564228.5:c.1519C>T
ENST00000564403.6:c.1762C>T
ENST00000564999.5:c.1732C>T
ENST00000565018.6:c.1480C>T
ENST00000566279.5:c.1564C>T
ENST00000566286.5:c.1723C>T
ENST00000567880.5:c.1552C>T
ENST00000568673.5:c.1672C>T
ENST00000568740.5:c.1657C>T
ENST00000570177.6:c.1342C>T
ENST00000570287.6:c.1252C>T
ENST00000616053.4:c.1480C>T
ENST00000626466.1:n.767C>T
ENST00000626584.2:c.1084C>T
ENST00000629387.2:c.1744C>T
NM_001083962.1:c.1744C>T
NM_001243226.2:c.2050C>T
NM_001243227.1:c.1672C>T
NM_001243228.1:c.1762C>T
NM_001243230.1:c.1723C>T
NM_001243231.1:c.1606C>T
NM_001243232.1:c.1531C>T
NM_001243233.1:c.1342C>T
NM_001243234.1:c.1264C>T
NM_001243235.1:c.1252C>T
NM_001243236.1:c.1252C>T
NM_001306207.1:c.1660C>T
NM_001306208.1:c.1519C>T
NM_003199.2:c.1732C>T
NM_001330604.2:c.1741C>T
NM_001330605.2:c.1354C>T
NM_001348211.1:c.1618C>T
NM_001348212.1:c.1342C>T
NM_001348213.1:c.1354C>T
NM_001348214.1:c.1249C>T
NM_001348215.1:c.1096C>T
NM_001348216.1:c.1264C>T
NM_001348217.1:c.1672C>T
NM_001348218.1:c.1672C>T
NM_001348219.1:c.1660C>T
NM_001348220.1:c.1657C>T
NM_001243226.3:c.2050C>T
NM_001243227.2:c.1672C>T
NM_001243228.2:c.1762C>T
NM_001243231.2:c.1606C>T
NM_001243233.2:c.1342C>T
NM_001243234.2:c.1264C>T
NM_001243235.2:c.1252C>T
NM_001243236.2:c.1252C>T
NM_001330604.3:c.1741C>T
NM_001330605.3:c.1354C>T
NM_001348211.2:c.1618C>T
NM_001348212.2:c.1342C>T
NM_001348213.2:c.1354C>T
NM_001348214.2:c.1249C>T
NM_001348215.2:c.1096C>T
NM_001348216.2:c.1264C>T
NM_001348218.2:c.1672C>T
NM_001348219.2:c.1660C>T
NM_001369567.1:c.1744C>T
NM_001369568.1:c.1744C>T
NM_001369569.1:c.1741C>T
NM_001369570.1:c.1741C>T
NM_001369571.1:c.1732C>T
NM_001369572.1:c.1732C>T
NM_001369573.1:c.1729C>T
NM_001369574.1:c.1729C>T
NM_001369575.1:c.1672C>T
NM_001369576.1:c.1669C>T
NM_001369577.1:c.1669C>T
NM_001369578.1:c.1669C>T
NM_001369579.1:c.1669C>T
NM_001369580.1:c.1669C>T
NM_001369581.1:c.1669C>T
NM_001369582.1:c.1660C>T
NM_001369583.1:c.1660C>T
NM_001369584.1:c.1657C>T
NM_001369585.1:c.1657C>T
NM_001369586.1:c.1675C>T
NM_003199.3:c.1732C>T
NM_001243230.2:c.1723C>T
More

Likely Pathogenic

Met criteria codes 5
PM2_Supporting PP3 PS4_Supporting PM5 PM1
Not Met criteria codes 1
PM6

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.Arg582Cys variant in TCF4 is absent from gnomAD (PM2_Supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg582Cys variant occurs in the well-characterized basic Helix-Loop-Helix domain (bHLH) functional domain of the TCF4 (PM1). A pathogenic missense variant (p.R582P) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 22460224, PMID 26621827, PMID 20184619, internal database) (PM5). The p.Arg582Cys variant in TCF4 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with an unspecified neurodevelopmental disorder (PMID 33994118). The p.Arg582Cys variant has been observed in at least 2 individuals with clinical features of Pitt-Hopkins syndrome (PMID 33994118, internal database) (PS4_Supporting). In summary, the p.Arg582Cys variant in TCF4 is classified as likely pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM2_Supporting, PP3, PM1, PM5, PS4_Supporting).
Met criteria codes
PM2_Supporting
The p.Arg582Cys variant in TCF4 is absent from gnomAD (PM2_Supporting).
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3).
PS4_Supporting
The p.Arg582Cys variant has been observed in at least 2 individuals with clinical features of Pitt-Hopkins syndrome (PMID 33994118, internal database) (PS4_Supporting).
PM5
A pathogenic missense variant (p.R582P) has been previously identified within this codon which indicates that this residue is critical to the function of the protein (PMID 22460224, PMID 26621827, PMID 20184619, internal database) (PM5). Criteria used for p.R582P: PM2_Supporting, PM1, PP3, PS3, PM6 (internal)
PM1
The p.Arg582Cys variant occurs in the well-characterized basic Helix-Loop-Helix domain (bHLH) functional domain of the TCF4 (PM1).
Not Met criteria codes
PM6
The p.Arg582Cys variant in TCF4 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with an unspecified neurodevelopmental disorder (PMID 33994118).
Curation History
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