Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_001083962.2(TCF4):c.1826T>C (p.Leu609Pro)

CA16608769

393171 (ClinVar)

Gene: TCF4 (HGNC:6925)

Condition: Pitt-Hopkins syndrome (MONDO:0012589)

Inheritance Mode: Autosomal dominant inheritance

UUID: 5d0fcac9-7b04-4d3f-92d8-91250132dcb7

Approved on: 2026-01-28

Published on: 2026-03-31

HGVS expressions

NM_001083962.2:c.1826T>C

NM_001083962.2(TCF4):c.1826T>C (p.Leu609Pro)

NC_000018.10:g.55228900A>G

CM000680.2:g.55228900A>G

NC_000018.9:g.52896131A>G

CM000680.1:g.52896131A>G

NC_000018.8:g.51047129A>G

NG_011716.1:g.364730T>C

NG_011716.2:g.412094T>C

ENST00000354452.8:c.1826T>C

ENST00000635822.2:c.1706T>C

ENST00000635990.2:n.1506T>C

ENST00000636400.2:c.1754T>C

ENST00000636751.2:c.*1534T>C

ENST00000636822.2:c.1436T>C

ENST00000637115.2:c.*1704T>C

ENST00000637169.2:c.1178T>C

ENST00000637239.2:n.1881T>C

ENST00000637250.2:n.1520T>C

ENST00000637923.2:c.1424T>C

ENST00000638154.3:c.1853T>C

ENST00000643689.1:c.1436T>C

ENST00000674764.1:c.*1437T>C

ENST00000675707.1:c.1436T>C

ENST00000354452.7:c.1826T>C

ENST00000356073.8:c.1814T>C

ENST00000398339.5:c.2132T>C

ENST00000457482.7:c.1346T>C

ENST00000537578.5:c.1754T>C

ENST00000537856.7:c.1424T>C

ENST00000540999.5:c.1742T>C

ENST00000543082.5:c.1688T>C

ENST00000544241.6:c.1613T>C

ENST00000561831.7:c.1334T>C

ENST00000561992.5:c.1424T>C

ENST00000562680.5:n.5349T>C

ENST00000564228.5:c.1601T>C

ENST00000564403.6:c.1844T>C

ENST00000564999.5:c.1814T>C

ENST00000565018.6:c.1562T>C

ENST00000566279.5:c.1646T>C

ENST00000566286.5:c.1805T>C

ENST00000567880.5:c.1634T>C

ENST00000568673.5:c.1754T>C

ENST00000568740.5:c.1739T>C

ENST00000570177.6:c.1424T>C

ENST00000570287.6:c.1334T>C

ENST00000616053.4:c.1562T>C

ENST00000626466.1:n.849T>C

ENST00000626584.2:c.1166T>C

ENST00000626631.1:c.56T>C

ENST00000629387.2:c.1826T>C

NM_001083962.1:c.1826T>C

NM_001243226.2:c.2132T>C

NM_001243227.1:c.1754T>C

NM_001243228.1:c.1844T>C

NM_001243230.1:c.1805T>C

NM_001243231.1:c.1688T>C

NM_001243232.1:c.1613T>C

NM_001243233.1:c.1424T>C

NM_001243234.1:c.1346T>C

NM_001243235.1:c.1334T>C

NM_001243236.1:c.1334T>C

NM_001306207.1:c.1742T>C

NM_001306208.1:c.1601T>C

NM_003199.2:c.1814T>C

NM_001330604.2:c.1823T>C

NM_001330605.2:c.1436T>C

NM_001348211.1:c.1700T>C

NM_001348212.1:c.1424T>C

NM_001348213.1:c.1436T>C

NM_001348214.1:c.1331T>C

NM_001348215.1:c.1178T>C

NM_001348216.1:c.1346T>C

NM_001348217.1:c.1754T>C

NM_001348218.1:c.1754T>C

NM_001348219.1:c.1742T>C

NM_001348220.1:c.1739T>C

NM_001243226.3:c.2132T>C

NM_001243227.2:c.1754T>C

NM_001243228.2:c.1844T>C

NM_001243231.2:c.1688T>C

NM_001243233.2:c.1424T>C

NM_001243234.2:c.1346T>C

NM_001243235.2:c.1334T>C

NM_001243236.2:c.1334T>C

NM_001330604.3:c.1823T>C

NM_001330605.3:c.1436T>C

NM_001348211.2:c.1700T>C

NM_001348212.2:c.1424T>C

NM_001348213.2:c.1436T>C

NM_001348214.2:c.1331T>C

NM_001348215.2:c.1178T>C

NM_001348216.2:c.1346T>C

NM_001348218.2:c.1754T>C

NM_001348219.2:c.1742T>C

NM_001369567.1:c.1826T>C

NM_001369568.1:c.1826T>C

NM_001369569.1:c.1823T>C

NM_001369570.1:c.1823T>C

NM_001369571.1:c.1814T>C

NM_001369572.1:c.1814T>C

NM_001369573.1:c.1811T>C

NM_001369574.1:c.1811T>C

NM_001369575.1:c.1754T>C

NM_001369576.1:c.1751T>C

NM_001369577.1:c.1751T>C

NM_001369578.1:c.1751T>C

NM_001369579.1:c.1751T>C

NM_001369580.1:c.1751T>C

NM_001369581.1:c.1751T>C

NM_001369582.1:c.1742T>C

NM_001369583.1:c.1742T>C

NM_001369584.1:c.1739T>C

NM_001369585.1:c.1739T>C

NM_001369586.1:c.1757T>C

NM_003199.3:c.1814T>C

NM_001243230.2:c.1805T>C

Likely Pathogenic

PP3 PM1 PS2 PM2_Supporting

Evidence Links 0

Expert Panel

Rett and Angelman-like Disorders VCEP

Criteria Specification Information

Criteria Specification: ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for TCF4 Version 5.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

Rett and Angelman-like Disorders VCEP

The p.Leu609Pro variant in TCF4 occurs in the de novo state (biological parentage confirmed) in an affected individual (GeneDx- internal database) (PS2). The p.Leu609Pro variant occurs in the well-characterized basic Helix-Loop-Helix domain (bHLH) functional domain of TCF4 (PM1). The p.Leu609Pro variant in TCF4 is absent from gnomAD v4.1 (PM2_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.Leu609Pro variant in TCF4 is classified as Likely Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PS2, PM1, PM2_supporting, PP3). (TCF4 Specifications v.5.0; curation approved on 01/28/2026)

PP3

Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own.

PM1

This variant is located in the basic Helix-Loop-Helix domain (bHLH).

PS2

The p.Leu609Pro variant in TCF4 occurs in the de novo state (biological parentage confirmed) in an affected individual (GeneDx- internal database) (PS2).

PM2_Supporting

The p.Leu609Pro variant in TCF4 is absent from gnomAD v4.1.

Curation History

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