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]
  • No Criteria Specification was provided in the publication event for the variant classifaction.
  • The Criteria Specification shown below is a best-estimate based on the VCEP, gene, disease, and publication date.

Variant: NM_001083962.1(TCF4):c.1738C>T (p.Arg580Trp)

CA254160

7370 (ClinVar)

Gene: TCF4 (HGNC:6925)
Condition: Pitt-Hopkins syndrome (MONDO:0012589)
Inheritance Mode: Autosomal dominant inheritance
UUID: b4b4e028-4434-4362-a57e-8a50ad94182f
Approved on: 2021-03-26
Published on: 2021-05-17

HGVS expressions

NM_001083962.1(TCF4):c.1738C>T (p.Arg580Trp)
NM_001083962.1:c.1738C>T
ENST00000354452.8:c.1738C>T
ENST00000635822.2:c.1618C>T
ENST00000635990.2:n.1418C>T
ENST00000636400.2:c.1666C>T
ENST00000636751.2:c.*1446C>T
ENST00000636822.2:c.1348C>T
ENST00000637115.2:c.*1616C>T
ENST00000637169.2:c.1090C>T
ENST00000637239.2:n.1793C>T
ENST00000637250.2:n.1432C>T
ENST00000637923.2:n.1336C>T
ENST00000638154.3:c.1765C>T
ENST00000643689.1:c.1348C>T
ENST00000674764.1:c.*1349C>T
ENST00000675707.1:c.1348C>T
ENST00000354452.7:c.1738C>T
ENST00000356073.8:c.1726C>T
ENST00000398339.5:c.2044C>T
ENST00000457482.7:c.1258C>T
ENST00000537578.5:c.1666C>T
ENST00000537856.7:c.1336C>T
ENST00000540999.5:c.1654C>T
ENST00000543082.5:c.1600C>T
ENST00000544241.6:c.1525C>T
ENST00000561831.7:c.1246C>T
ENST00000561992.5:c.1336C>T
ENST00000562680.5:n.5261C>T
ENST00000564228.5:n.1513C>T
ENST00000564403.6:c.1756C>T
ENST00000564999.5:c.1726C>T
ENST00000565018.6:c.1474C>T
ENST00000566279.5:c.1558C>T
ENST00000566286.5:n.1717C>T
ENST00000567880.5:n.1546C>T
ENST00000568673.5:c.1666C>T
ENST00000568740.5:c.1651C>T
ENST00000570177.6:c.1336C>T
ENST00000570287.6:c.1246C>T
ENST00000616053.4:c.1474C>T
ENST00000626466.1:n.761C>T
ENST00000626584.2:c.1078C>T
ENST00000629387.2:c.1738C>T
NM_001243226.2:c.2044C>T
NM_001243227.1:c.1666C>T
NM_001243228.1:c.1756C>T
NM_001243230.1:c.1717C>T
NM_001243231.1:c.1600C>T
NM_001243232.1:c.1525C>T
NM_001243233.1:c.1336C>T
NM_001243234.1:c.1258C>T
NM_001243235.1:c.1246C>T
NM_001243236.1:c.1246C>T
NM_001306207.1:c.1654C>T
NM_001306208.1:c.1513C>T
NM_003199.2:c.1726C>T
NM_001330604.2:c.1735C>T
NM_001330605.2:c.1348C>T
NM_001348211.1:c.1612C>T
NM_001348212.1:c.1336C>T
NM_001348213.1:c.1348C>T
NM_001348214.1:c.1243C>T
NM_001348215.1:c.1090C>T
NM_001348216.1:c.1258C>T
NM_001348217.1:c.1666C>T
NM_001348218.1:c.1666C>T
NM_001348219.1:c.1654C>T
NM_001348220.1:c.1651C>T
NM_001083962.2:c.1738C>T
NM_001243226.3:c.2044C>T
NM_001243227.2:c.1666C>T
NM_001243228.2:c.1756C>T
NM_001243231.2:c.1600C>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_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_001348218.2:c.1666C>T
NM_001348219.2:c.1654C>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
NM_001243230.2:c.1717C>T
NC_000018.10:g.55228988G>A
CM000680.2:g.55228988G>A
NC_000018.9:g.52896219G>A
CM000680.1:g.52896219G>A
NC_000018.8:g.51047217G>A
NG_011716.1:g.364642C>T
NG_011716.2:g.412006C>T
More

Pathogenic

Met criteria codes 7
PM1 PM6_Strong PP4 PP3 PM2_Supporting PS4_Supporting PS3_Supporting

Evidence Links 1

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The p.Arg580Trp variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 17436254, 22045651) (PM6_strong, PS4_supporting, PP4). The p.Arg580Trp in TCF4 is absent from gnomAD (PM2_supporting). The p.Arg580Trp variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). In vitro binding assays have shown that this variant impacts protein function (PMID 22460224) (PS3_supporting). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg580Trp variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PM2_supporting, PS4_supporting, PP3, PP4).
Met criteria codes
PM1
The p.Arg580Trp variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4.
PM6_Strong
The p.Arg580Trp variant in TCF4 has been reported in at least 2 unconfirmed de novo occurrences in individuals with Pitt-Hopkins syndrome (as p.R576W in PMID 17436254).
The p.Arg580Trp variant (reported as as p.R576W) in TCF4 has been reported in 2 unconfirmed de novo occurrences in individuals with Pitt-Hopkins syndrome. PubMed:17436254
PP4
The p.Arg580Trp variant in TCF4 has been reported in at least 2 unconfirmed de novo occurrences in individuals with Pitt-Hopkins syndrome (as p.R576W in PMID 17436254).
The p.Arg580Trp variant in TCF4 has been reported in at least 2 unconfirmed de novo occurrences in individuals with Pitt-Hopkins syndrome PubMed:17436254
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own.
PM2_Supporting
The p.Arg580Trp in TCF4 is absent from gnomAD.
PS4_Supporting
The p.Arg580Trp variant in TCF4 has been reported in at least 2 unconfirmed de novo occurrences in individuals with Pitt-Hopkins syndrome (as p.R576W in PMID 17436254).
The p.Arg580Trp variant in TCF4 has been reported in at least 2 unconfirmed de novo occurrences in individuals with Pitt-Hopkins syndrome PubMed:17436254
PS3_Supporting
In vitro binding assays have shown that this variant impacts homodimer and heterodimer formation (PMID 22460224).
Curation History
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