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.1727G>A (p.Arg576Gln)

CA16607615

381549 (ClinVar)

Gene: TCF4 (HGNC:6925)
Condition: Pitt-Hopkins syndrome (MONDO:0012589)
Inheritance Mode: Autosomal dominant inheritance
UUID: b79ddda3-bf1e-4cee-8b49-6cc1423ac1a7
Approved on: 2021-03-26
Published on: 2021-05-17

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
More

Pathogenic

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

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
PM1
The p.Arg576Gln variant occurs in the well-characterized basic Helix-Loop-Helix domain of TCF4.
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.
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.
PS3_Supporting
In vitro binding assays have shown that this variant impacts homodimer and heterodimer formation (PMID 22460224).
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
ClinGen Terms of Use.
¤ Powered by BCM's Genboree.