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.759C>G (p.Ser253Arg)

CA402701458

432062 (ClinVar)

Gene: TCF4 (HGNC:6925)

Condition: Pitt-Hopkins syndrome (MONDO:0012589)

Inheritance Mode: Autosomal dominant inheritance

UUID: 1c53d5a5-faa3-4994-be9b-d5aef8d0405c

Approved on: 2026-01-28

Published on: 2026-03-31

HGVS expressions

NM_001083962.2:c.759C>G

NM_001083962.2(TCF4):c.759C>G (p.Ser253Arg)

NC_000018.10:g.55275649G>C

CM000680.2:g.55275649G>C

NC_000018.9:g.52942880G>C

CM000680.1:g.52942880G>C

NC_000018.8:g.51093878G>C

NG_011716.1:g.317981C>G

NG_011716.2:g.365345C>G

ENST00000354452.8:c.759C>G

ENST00000630720.3:c.279C>G

ENST00000635822.2:c.759C>G

ENST00000635990.2:n.439C>G

ENST00000636400.2:c.687C>G

ENST00000636751.2:c.*467C>G

ENST00000636822.2:c.369C>G

ENST00000637115.2:c.*649C>G

ENST00000637169.2:c.111C>G

ENST00000637239.2:n.826C>G

ENST00000637250.2:n.453C>G

ENST00000637923.2:c.357C>G

ENST00000638154.3:c.789C>G

ENST00000643689.1:c.369C>G

ENST00000674764.1:c.*370C>G

ENST00000675707.1:c.369C>G

ENST00000354452.7:c.759C>G

ENST00000356073.8:c.759C>G

ENST00000398339.5:c.1065C>G

ENST00000457482.7:c.279C>G

ENST00000537578.5:c.687C>G

ENST00000537856.7:c.369C>G

ENST00000540999.5:c.687C>G

ENST00000543082.5:c.633C>G

ENST00000544241.6:c.546C>G

ENST00000561831.7:c.279C>G

ENST00000561992.5:c.369C>G

ENST00000562030.3:c.369C>G

ENST00000562607.5:c.369C>G

ENST00000562680.5:n.850C>G

ENST00000563686.5:n.614C>G

ENST00000563760.5:n.351C>G

ENST00000564228.5:c.546C>G

ENST00000564403.6:c.777C>G

ENST00000564999.5:c.759C>G

ENST00000565018.6:c.507C>G

ENST00000565580.3:n.508C>G

ENST00000566279.5:c.579C>G

ENST00000566286.5:c.753C>G

ENST00000566514.5:c.720C>G

ENST00000566777.5:c.369C>G

ENST00000567880.5:c.579C>G

ENST00000568169.5:c.771C>G

ENST00000568673.5:c.687C>G

ENST00000568740.5:c.684C>G

ENST00000569012.5:c.369C>G

ENST00000570146.3:c.23C>G

ENST00000570177.6:c.369C>G

ENST00000570287.6:c.279C>G

ENST00000616053.4:c.507C>G

ENST00000625849.2:n.619C>G

ENST00000625925.2:c.369C>G

ENST00000626584.2:c.111C>G

ENST00000627136.2:n.524-14116C>G

ENST00000628078.2:c.369C>G

ENST00000628636.2:c.369C>G

ENST00000628689.2:c.175+3902C>G

ENST00000629343.2:c.369C>G

ENST00000629387.2:c.759C>G

ENST00000630268.2:c.369C>G

ENST00000630319.2:c.528C>G

ENST00000630712.2:c.369C>G

ENST00000630720.2:c.279C>G

ENST00000630828.2:c.549C>G

NM_001083962.1:c.759C>G

NM_001243226.2:c.1065C>G

NM_001243227.1:c.687C>G

NM_001243228.1:c.777C>G

NM_001243230.1:c.753C>G

NM_001243231.1:c.633C>G

NM_001243232.1:c.546C>G

NM_001243233.1:c.369C>G

NM_001243234.1:c.279C>G

NM_001243235.1:c.279C>G

NM_001243236.1:c.279C>G

NM_001306207.1:c.687C>G

NM_001306208.1:c.546C>G

NM_003199.2:c.759C>G

NM_001330604.2:c.759C>G

NM_001330605.2:c.369C>G

NM_001348211.1:c.633C>G

NM_001348212.1:c.369C>G

NM_001348213.1:c.369C>G

NM_001348214.1:c.279C>G

NM_001348215.1:c.111C>G

NM_001348216.1:c.279C>G

NM_001348217.1:c.687C>G

NM_001348218.1:c.687C>G

NM_001348219.1:c.687C>G

NM_001348220.1:c.684C>G

NM_001243226.3:c.1065C>G

NM_001243227.2:c.687C>G

NM_001243228.2:c.777C>G

NM_001243231.2:c.633C>G

NM_001243233.2:c.369C>G

NM_001243234.2:c.279C>G

NM_001243235.2:c.279C>G

NM_001243236.2:c.279C>G

NM_001330604.3:c.759C>G

NM_001330605.3:c.369C>G

NM_001348211.2:c.633C>G

NM_001348212.2:c.369C>G

NM_001348213.2:c.369C>G

NM_001348214.2:c.279C>G

NM_001348215.2:c.111C>G

NM_001348216.2:c.279C>G

NM_001348218.2:c.687C>G

NM_001348219.2:c.687C>G

NM_001369567.1:c.759C>G

NM_001369568.1:c.759C>G

NM_001369569.1:c.756C>G

NM_001369570.1:c.756C>G

NM_001369571.1:c.759C>G

NM_001369572.1:c.759C>G

NM_001369573.1:c.756C>G

NM_001369574.1:c.759C>G

NM_001369575.1:c.687C>G

NM_001369576.1:c.684C>G

NM_001369577.1:c.687C>G

NM_001369578.1:c.684C>G

NM_001369579.1:c.687C>G

NM_001369580.1:c.687C>G

NM_001369581.1:c.684C>G

NM_001369582.1:c.687C>G

NM_001369583.1:c.687C>G

NM_001369584.1:c.684C>G

NM_001369585.1:c.684C>G

NM_001369586.1:c.687C>G

NM_003199.3:c.759C>G

NM_001243230.2:c.753C>G

Pathogenic

PS2_Very Strong PS4_Moderate PM2_Supporting PP4

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.Ser253Arg variant in TCF4 has been observed as a de novo occurrence (biological parentage both confirmed and unconfirmed) in 3 individuals with features of Pitt-Hopkins syndrome (PMID 29322350; PMID 26993267, described as p.Ser355Arg; University of Chicago-internal database) (PS2_Very strong). The p.Ser253Arg variant has been observed in 3 individuals with Pitt-Hopkins syndrome (PMID 29322350; 26993267, described as p.Ser355Arg) (PS4_Moderate, PP4). The p.Ser253Arg variant in TCF4 is absent from gnomAD v4.1 (PM2_Supporting). In summary, the p.Ser253Arg variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PS2_Very strong, PS4_moderate, PM2_supporting, PP4). (TCF4 Specifications v.5.0; curation approved on 01/28/2026).

PS2_Very Strong

The p.Ser253Arg variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in an individual with Pitt-Hopkins syndrome (PMID 29322350) (PS2_Very strong).

PS4_Moderate

The p.Ser253Arg variant has been observed in 3 other individuals with Pitt-Hopkins syndrome (PMIDs 29322350; 26993267, described as p.Ser355Arg)

PM2_Supporting

The p.Ser253Arg variant in TCF4 is absent from gnomAD v4.1.

PP4

The p.Ser253Arg variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt–Hopkins syndrome (PMID: 26993267, described as p.Ser355Arg).

Curation History

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