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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  • See Evidence submitted by expert panel for details.

Variant: NM_001083962.2(TCF4):c.1733G>A (p.Arg578His)

CA266820

93542 (ClinVar)

Gene: TCF4
Condition: Pitt-Hopkins syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: b545bd8e-c8f6-4437-a1d0-ce19966d9ce7
Approved on: 2021-03-26
Published on: 2021-05-17

HGVS expressions

NM_001083962.2:c.1733G>A
NM_001083962.2(TCF4):c.1733G>A (p.Arg578His)
ENST00000354452.8:c.1733G>A
ENST00000635822.2:c.1613G>A
ENST00000635990.2:n.1413G>A
ENST00000636400.2:c.1661G>A
ENST00000636751.2:c.*1441G>A
ENST00000636822.2:c.1343G>A
ENST00000637115.2:c.*1611G>A
ENST00000637169.2:c.1085G>A
ENST00000637239.2:n.1788G>A
ENST00000637250.2:n.1427G>A
ENST00000637923.2:n.1331G>A
ENST00000638154.3:c.1760G>A
ENST00000643689.1:c.1343G>A
ENST00000674764.1:c.*1344G>A
ENST00000675707.1:c.1343G>A
ENST00000354452.7:c.1733G>A
ENST00000356073.8:c.1721G>A
ENST00000398339.5:c.2039G>A
ENST00000457482.7:c.1253G>A
ENST00000537578.5:c.1661G>A
ENST00000537856.7:c.1331G>A
ENST00000540999.5:c.1649G>A
ENST00000543082.5:c.1595G>A
ENST00000544241.6:c.1520G>A
ENST00000561831.7:c.1241G>A
ENST00000561992.5:c.1331G>A
ENST00000562680.5:n.5256G>A
ENST00000564228.5:n.1508G>A
ENST00000564403.6:c.1751G>A
ENST00000564999.5:c.1721G>A
ENST00000565018.6:c.1469G>A
ENST00000566279.5:c.1553G>A
ENST00000566286.5:n.1712G>A
ENST00000567880.5:n.1541G>A
ENST00000568673.5:c.1661G>A
ENST00000568740.5:c.1646G>A
ENST00000570177.6:c.1331G>A
ENST00000570287.6:c.1241G>A
ENST00000616053.4:c.1469G>A
ENST00000626466.1:n.756G>A
ENST00000626584.2:c.1073G>A
ENST00000629387.2:c.1733G>A
NM_001083962.1:c.1733G>A
NM_001243226.2:c.2039G>A
NM_001243227.1:c.1661G>A
NM_001243228.1:c.1751G>A
NM_001243230.1:c.1712G>A
NM_001243231.1:c.1595G>A
NM_001243232.1:c.1520G>A
NM_001243233.1:c.1331G>A
NM_001243234.1:c.1253G>A
NM_001243235.1:c.1241G>A
NM_001243236.1:c.1241G>A
NM_001306207.1:c.1649G>A
NM_001306208.1:c.1508G>A
NM_003199.2:c.1721G>A
NM_001330604.2:c.1730G>A
NM_001330605.2:c.1343G>A
NM_001348211.1:c.1607G>A
NM_001348212.1:c.1331G>A
NM_001348213.1:c.1343G>A
NM_001348214.1:c.1238G>A
NM_001348215.1:c.1085G>A
NM_001348216.1:c.1253G>A
NM_001348217.1:c.1661G>A
NM_001348218.1:c.1661G>A
NM_001348219.1:c.1649G>A
NM_001348220.1:c.1646G>A
NM_001243226.3:c.2039G>A
NM_001243227.2:c.1661G>A
NM_001243228.2:c.1751G>A
NM_001243231.2:c.1595G>A
NM_001243233.2:c.1331G>A
NM_001243234.2:c.1253G>A
NM_001243235.2:c.1241G>A
NM_001243236.2:c.1241G>A
NM_001330604.3:c.1730G>A
NM_001330605.3:c.1343G>A
NM_001348211.2:c.1607G>A
NM_001348212.2:c.1331G>A
NM_001348213.2:c.1343G>A
NM_001348214.2:c.1238G>A
NM_001348215.2:c.1085G>A
NM_001348216.2:c.1253G>A
NM_001348218.2:c.1661G>A
NM_001348219.2:c.1649G>A
NM_001369567.1:c.1733G>A
NM_001369568.1:c.1733G>A
NM_001369569.1:c.1730G>A
NM_001369570.1:c.1730G>A
NM_001369571.1:c.1721G>A
NM_001369572.1:c.1721G>A
NM_001369573.1:c.1718G>A
NM_001369574.1:c.1718G>A
NM_001369575.1:c.1661G>A
NM_001369576.1:c.1658G>A
NM_001369577.1:c.1658G>A
NM_001369578.1:c.1658G>A
NM_001369579.1:c.1658G>A
NM_001369580.1:c.1658G>A
NM_001369581.1:c.1658G>A
NM_001369582.1:c.1649G>A
NM_001369583.1:c.1649G>A
NM_001369584.1:c.1646G>A
NM_001369585.1:c.1646G>A
NM_001369586.1:c.1664G>A
NM_003199.3:c.1721G>A
NM_001243230.2:c.1712G>A
NC_000018.10:g.55228993C>T
CM000680.2:g.55228993C>T
NC_000018.9:g.52896224C>T
CM000680.1:g.52896224C>T
NC_000018.8:g.51047222C>T
NG_011716.1:g.364637G>A
NG_011716.2:g.412001G>A

Pathogenic

Met criteria codes 7
PS4_Moderate PM2_Supporting PM6_Strong PP3 PP4 PS3_Supporting 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.Arg578His variant in TCF4 has been reported in an individual with a clinical phenotype suggestive of Pitt-Hopkins syndrome (PMID 18728071) (PP4). This variant appears to be de novo in this patient and has been reported in the de novo state (biological parentage unconfirmed) in at least two additional patients with Pitt-Hopkins syndrome (PMID 21671391) (PM6_strong, PS4_moderate). In vitro binding assays have shown that this variant impacts impacts protein function (PMID 22460224) (PS3_supporting). This variant is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651) (PM1). Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own (PP3). The p.Arg578His variant in TCF4 is absent from gnomAD (PM2_supporting). In summary, the Arg578His variant in TCF4 is classified as Pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM6_strong, PS4_moderate, PM1, PM2_supporting, PP3, PP4).
Met criteria codes
PS4_Moderate
The p.Arg578His variant in TCF4 has been observed in 3 affected individuals (PMID 18728071, 21671391).
Observed in 2 individuals with Pitt-Hopkins PubMed:21671391
Observed in 1 individual with Pitt-Hopkins PubMed:18728071
PM2_Supporting
The p.Arg578His variant in TCF4 is absent from gnomAD.
PM6_Strong
The p.Arg578His variant in TCF4 has been reported as an unconfirmed de novo occurrence in at least 3 individuals with Pitt-Hopkins syndrome (PMID 18728071, 21671391).
The p.Arg578His variant in TCF4 has been reported as an unconfirmed de novo occurrence in 2 individuals with Pitt-Hopkins syndrome (PMID 21671391). PubMed:21671391
The p.Arg578His variant in TCF4 has been reported as a confirmed de novo occurrence in an individual with Pitt-Hopkins syndrome (PMID 18728071). PubMed:18728071
PP3
Computational prediction analysis tools suggests a deleterious impact; however, this information does not predict clinical significance on its own.
PP4
The p.Arg578His variant in TCF4 has been reported de novo occurrence in at least 2 individuals with Pitt-Hopkins syndrome (PMID 18728071, 21671391).
The p.Arg578His variant in TCF4 has been reported as an unconfirmed de novo occurrence in 2 individuals with Pitt-Hopkins syndrome (PMID 21671391). PubMed:21671391
The p.Arg578His variant in TCF4 has been reported as a confirmed de novo occurrence in an individual with Pitt-Hopkins syndrome (PMID 18728071) PubMed:18728071
PS3_Supporting
In vitro binding assays have shown that this variant impacts homodimer and heterodimer formation (PMID 22460224).
PM1
This variant is located in the basic Helix-Loop-Helix domain (bHLH) (PMID 17436254, 22045651)
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