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_001083962.1(TCF4):c.1727G>A (p.Arg576Gln)

CA16607615

381549 (ClinVar)

Gene: TCF4
Condition: Pitt-Hopkins syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b79ddda3-bf1e-4cee-8b49-6cc1423ac1a7

HGVS expressions

NM_001083962.1:c.1727G>A
NM_001083962.1(TCF4):c.1727G>A (p.Arg576Gln)
NC_000018.10:g.55228999C>T
CM000680.2:g.55228999C>T
NC_000018.9:g.52896230C>T
CM000680.1:g.52896230C>T
NC_000018.8:g.51047228C>T
NG_011716.1:g.364631G>A
NG_011716.2:g.411995G>A
ENST00000354452.8:c.1727G>A
ENST00000635822.2:c.1607G>A
ENST00000635990.2:n.1407G>A
ENST00000636400.2:c.1655G>A
ENST00000636751.2:c.*1435G>A
ENST00000636822.2:c.1337G>A
ENST00000637115.2:c.*1605G>A
ENST00000637169.2:c.1079G>A
ENST00000637239.2:n.1782G>A
ENST00000637250.2:n.1421G>A
ENST00000637923.2:n.1325G>A
ENST00000638154.3:c.1754G>A
ENST00000643689.1:c.1337G>A
ENST00000674764.1:c.*1338G>A
ENST00000675707.1:c.1337G>A
ENST00000354452.7:c.1727G>A
ENST00000356073.8:c.1715G>A
ENST00000398339.5:c.2033G>A
ENST00000457482.7:c.1247G>A
ENST00000537578.5:c.1655G>A
ENST00000537856.7:c.1325G>A
ENST00000540999.5:c.1643G>A
ENST00000543082.5:c.1589G>A
ENST00000544241.6:c.1514G>A
ENST00000561831.7:c.1235G>A
ENST00000561992.5:c.1325G>A
ENST00000562680.5:n.5250G>A
ENST00000564228.5:n.1502G>A
ENST00000564403.6:c.1745G>A
ENST00000564999.5:c.1715G>A
ENST00000565018.6:c.1463G>A
ENST00000566279.5:c.1547G>A
ENST00000566286.5:n.1706G>A
ENST00000567880.5:n.1535G>A
ENST00000568673.5:c.1655G>A
ENST00000568740.5:c.1640G>A
ENST00000570177.6:c.1325G>A
ENST00000570287.6:c.1235G>A
ENST00000616053.4:c.1463G>A
ENST00000626466.1:n.750G>A
ENST00000626584.2:c.1067G>A
ENST00000629387.2:c.1727G>A
NM_001243226.2:c.2033G>A
NM_001243227.1:c.1655G>A
NM_001243228.1:c.1745G>A
NM_001243230.1:c.1706G>A
NM_001243231.1:c.1589G>A
NM_001243232.1:c.1514G>A
NM_001243233.1:c.1325G>A
NM_001243234.1:c.1247G>A
NM_001243235.1:c.1235G>A
NM_001243236.1:c.1235G>A
NM_001306207.1:c.1643G>A
NM_001306208.1:c.1502G>A
NM_003199.2:c.1715G>A
NM_001330604.2:c.1724G>A
NM_001330605.2:c.1337G>A
NM_001348211.1:c.1601G>A
NM_001348212.1:c.1325G>A
NM_001348213.1:c.1337G>A
NM_001348214.1:c.1232G>A
NM_001348215.1:c.1079G>A
NM_001348216.1:c.1247G>A
NM_001348217.1:c.1655G>A
NM_001348218.1:c.1655G>A
NM_001348219.1:c.1643G>A
NM_001348220.1:c.1640G>A
NM_001083962.2:c.1727G>A
NM_001243226.3:c.2033G>A
NM_001243227.2:c.1655G>A
NM_001243228.2:c.1745G>A
NM_001243231.2:c.1589G>A
NM_001243233.2:c.1325G>A
NM_001243234.2:c.1247G>A
NM_001243235.2:c.1235G>A
NM_001243236.2:c.1235G>A
NM_001330604.3:c.1724G>A
NM_001330605.3:c.1337G>A
NM_001348211.2:c.1601G>A
NM_001348212.2:c.1325G>A
NM_001348213.2:c.1337G>A
NM_001348214.2:c.1232G>A
NM_001348215.2:c.1079G>A
NM_001348216.2:c.1247G>A
NM_001348218.2:c.1655G>A
NM_001348219.2:c.1643G>A
NM_001369567.1:c.1727G>A
NM_001369568.1:c.1727G>A
NM_001369569.1:c.1724G>A
NM_001369570.1:c.1724G>A
NM_001369571.1:c.1715G>A
NM_001369572.1:c.1715G>A
NM_001369573.1:c.1712G>A
NM_001369574.1:c.1712G>A
NM_001369575.1:c.1655G>A
NM_001369576.1:c.1652G>A
NM_001369577.1:c.1652G>A
NM_001369578.1:c.1652G>A
NM_001369579.1:c.1652G>A
NM_001369580.1:c.1652G>A
NM_001369581.1:c.1652G>A
NM_001369582.1:c.1643G>A
NM_001369583.1:c.1643G>A
NM_001369584.1:c.1640G>A
NM_001369585.1:c.1640G>A
NM_001369586.1:c.1658G>A
NM_003199.3:c.1715G>A
NM_001243230.2:c.1706G>A

Pathogenic

Met criteria codes 7
PS3_Supporting PS2_Very Strong PS4_Supporting PM2_Supporting PP4 PP3 PM1

Evidence Links 2

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
Rett and Angelman-like Disorders VCEP
The p.Arg576Gln variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in at least 2 individuals with Pitt-Hopkins syndrome (PMID 23033978, 28726809) (PS2_VS, PS4_supporting, PP4). The p.Arg576Gln variant in TCF4 is absent from gnomAD (PM2_supporting). In vitro binding assays have shown that this variant impacts protein function (PMID 22460224) (PS3_supporting). The p.Arg576Gln 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.Arg576Gln variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PS2_VS, PM1, PS4_supporting, PM2_supporting, PP3, PP4).
Met criteria codes
PS3_Supporting
In vitro binding assays have shown that this variant impacts homodimer and heterodimer formation (PMID 22460224).
PS2_Very Strong
The p.Arg576Gln in TCF4 has been reported as a confirmed de novo occurrence in at least 2 individuals with Pitt-Hopkins syndrome (PMID 23033978 and 28726809).
The p.Arg576Gln in TCF4 has been reported as a de novo occurrence as part of an exome trio in an individual with Pitt-Hopkins syndrome. PubMed:28726809
The p.Arg576Gln in TCF4 has been reported as a de novo occurrence as part of an exome trio in an individual with severe intellectual disability. PubMed:23033978
PS4_Supporting
Found in two patients with Pitt-Hopkins syndrome
Found in affected individual PubMed:23033978
Found in affected individual PubMed:28726809
PM2_Supporting
The p.Arg576Gln in TCF4 is absent from gnomAD.
PP4
The p.Arg576Gln in TCF4 has been reported as a confirmed de novo occurrence in at least 2 individuals with Pitt-Hopkins syndrome (PMID 23033978 and 28726809).
Found in patient with Pitt-Hopkins syndrome PubMed:28726809
Found in patient with Pitt-Hopkins syndrome PubMed:23033978
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own.
PM1
The p.Arg576Gln variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4.
Approved on: 2021-03-26
Published on: 2021-05-17
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