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]
  • See Evidence submitted by expert panel for details.

Variant: NM_001083962.1(TCF4):c.1739G>A (p.Arg580Gln)

CA254162

7371 (ClinVar)

Gene: TCF4
Condition: Pitt-Hopkins syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 23eb4bab-14dd-4fbb-aebc-7c755b2976ea
Approved on: 2021-03-26
Published on: 2021-05-17

HGVS expressions

NM_001083962.1:c.1739G>A
NM_001083962.1(TCF4):c.1739G>A (p.Arg580Gln)
ENST00000354452.8:c.1739G>A
ENST00000635822.2:c.1619G>A
ENST00000635990.2:n.1419G>A
ENST00000636400.2:c.1667G>A
ENST00000636751.2:c.*1447G>A
ENST00000636822.2:c.1349G>A
ENST00000637115.2:c.*1617G>A
ENST00000637169.2:c.1091G>A
ENST00000637239.2:n.1794G>A
ENST00000637250.2:n.1433G>A
ENST00000637923.2:n.1337G>A
ENST00000638154.3:c.1766G>A
ENST00000643689.1:c.1349G>A
ENST00000674764.1:c.*1350G>A
ENST00000675707.1:c.1349G>A
ENST00000354452.7:c.1739G>A
ENST00000356073.8:c.1727G>A
ENST00000398339.5:c.2045G>A
ENST00000457482.7:c.1259G>A
ENST00000537578.5:c.1667G>A
ENST00000537856.7:c.1337G>A
ENST00000540999.5:c.1655G>A
ENST00000543082.5:c.1601G>A
ENST00000544241.6:c.1526G>A
ENST00000561831.7:c.1247G>A
ENST00000561992.5:c.1337G>A
ENST00000562680.5:n.5262G>A
ENST00000564228.5:n.1514G>A
ENST00000564403.6:c.1757G>A
ENST00000564999.5:c.1727G>A
ENST00000565018.6:c.1475G>A
ENST00000566279.5:c.1559G>A
ENST00000566286.5:n.1718G>A
ENST00000567880.5:n.1547G>A
ENST00000568673.5:c.1667G>A
ENST00000568740.5:c.1652G>A
ENST00000570177.6:c.1337G>A
ENST00000570287.6:c.1247G>A
ENST00000616053.4:c.1475G>A
ENST00000626466.1:n.762G>A
ENST00000626584.2:c.1079G>A
ENST00000629387.2:c.1739G>A
NM_001243226.2:c.2045G>A
NM_001243227.1:c.1667G>A
NM_001243228.1:c.1757G>A
NM_001243230.1:c.1718G>A
NM_001243231.1:c.1601G>A
NM_001243232.1:c.1526G>A
NM_001243233.1:c.1337G>A
NM_001243234.1:c.1259G>A
NM_001243235.1:c.1247G>A
NM_001243236.1:c.1247G>A
NM_001306207.1:c.1655G>A
NM_001306208.1:c.1514G>A
NM_003199.2:c.1727G>A
NM_001330604.2:c.1736G>A
NM_001330605.2:c.1349G>A
NM_001348211.1:c.1613G>A
NM_001348212.1:c.1337G>A
NM_001348213.1:c.1349G>A
NM_001348214.1:c.1244G>A
NM_001348215.1:c.1091G>A
NM_001348216.1:c.1259G>A
NM_001348217.1:c.1667G>A
NM_001348218.1:c.1667G>A
NM_001348219.1:c.1655G>A
NM_001348220.1:c.1652G>A
NM_001083962.2:c.1739G>A
NM_001243226.3:c.2045G>A
NM_001243227.2:c.1667G>A
NM_001243228.2:c.1757G>A
NM_001243231.2:c.1601G>A
NM_001243233.2:c.1337G>A
NM_001243234.2:c.1259G>A
NM_001243235.2:c.1247G>A
NM_001243236.2:c.1247G>A
NM_001330604.3:c.1736G>A
NM_001330605.3:c.1349G>A
NM_001348211.2:c.1613G>A
NM_001348212.2:c.1337G>A
NM_001348213.2:c.1349G>A
NM_001348214.2:c.1244G>A
NM_001348215.2:c.1091G>A
NM_001348216.2:c.1259G>A
NM_001348218.2:c.1667G>A
NM_001348219.2:c.1655G>A
NM_001369567.1:c.1739G>A
NM_001369568.1:c.1739G>A
NM_001369569.1:c.1736G>A
NM_001369570.1:c.1736G>A
NM_001369571.1:c.1727G>A
NM_001369572.1:c.1727G>A
NM_001369573.1:c.1724G>A
NM_001369574.1:c.1724G>A
NM_001369575.1:c.1667G>A
NM_001369576.1:c.1664G>A
NM_001369577.1:c.1664G>A
NM_001369578.1:c.1664G>A
NM_001369579.1:c.1664G>A
NM_001369580.1:c.1664G>A
NM_001369581.1:c.1664G>A
NM_001369582.1:c.1655G>A
NM_001369583.1:c.1655G>A
NM_001369584.1:c.1652G>A
NM_001369585.1:c.1652G>A
NM_001369586.1:c.1670G>A
NM_003199.3:c.1727G>A
NM_001243230.2:c.1718G>A
NC_000018.10:g.55228987C>T
CM000680.2:g.55228987C>T
NC_000018.9:g.52896218C>T
CM000680.1:g.52896218C>T
NC_000018.8:g.51047216C>T
NG_011716.1:g.364643G>A
NG_011716.2:g.412007G>A
More

Pathogenic

Met criteria codes 7
PM2_Supporting PP4 PP3 PM1 PS3_Supporting PM6_Strong PS4_Supporting

Evidence Links 3

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The p.Arg580Gln variant in TCF4 has been reported in at least 2 de novo occurrences (biological parentage unconfirmed) in individuals with Pitt-Hopkins syndrome (PMID 22045651, 17436254) (PM6_strong, PS4_supporting, PP4). Transcriptional reporter assay has shown that this variant impacts protein function (PMID 19235238) (PS3_supporting). The p.Arg580Gln variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4 (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). In summary, the p.Arg580Gln variant in TCF4 is classified as Pathogenic for autosomal dominant Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PM1, PS4_supporting, PP1, PP3, PP4).
Met criteria codes
PM2_Supporting
The p.Arg580Gln variant in TCF4 is absent from gnomAD.
PP4
The p.Arg580Gln variant in TCF4 has been reported in at least 2 unconfirmed de novo occurrences in individuals with Pitt-Hopkins syndrome (PMID 22045651 and as p.R576Q in PMID 17436254).
The p.Arg580Gln variant (reported as p.R576Q) in TCF4 has been reported in an unconfirmed de novo occurrences in an individual with Pitt-Hopkins syndrome. PubMed:17436254
The p.Arg580Gln variant in TCF4 has been reported in an unconfirmed de novo occurrences in an individual with Pitt-Hopkins syndrome. PubMed:22045651
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own.
PM1
The p.Arg580Gln variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4.
PS3_Supporting
Transcriptional reporter assay has shown that this variant impacts protein function (PMID 19235238).
Functional studies using a luciferase reporter assay showed that this variant activity is significantly lower than wild-type heterodimers. PubMed:19235238
PM6_Strong
The p.Arg580Gln variant in TCF4 has been reported in at least 2 unconfirmed de novo occurrences in individuals with Pitt-Hopkins syndrome (PMID 22045651 and as p.R576Q in PMID 17436254).
The p.Arg580Gln variant (reported as p.R576Q) in TCF4 has been reported in an unconfirmed de novo occurrences in an individual with Pitt-Hopkins syndrome. PubMed:17436254
The p.Arg580Gln variant in TCF4 has been reported in an unconfirmed de novo occurrences in an individual with Pitt-Hopkins syndrome. PubMed:22045651
PS4_Supporting
The p.Arg580Gln variant in TCF4 has been reported in at least 2 unconfirmed de novo occurrences in individuals with Pitt-Hopkins syndrome (PMID 22045651 and as p.R576Q in PMID 17436254).
Reported in 1 individual with Pitt-Hopkins PubMed:17436254
Reported in 1 individual with Pitt-Hopkins PubMed:22045651
Curation History
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