Submissions for variant NM_001083962.2(TCF4):c.1245T>C (p.His415=)

gnomAD frequency: 0.00006  dbSNP: rs148909575

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV002517681	SCV005440652	likely benign	Pitt-Hopkins syndrome	2024-06-25	reviewed by expert panel	curation	The highest population minor allele frequency of the c.1245T>C (p.His415His) variant in TCF4 in gnomAD v2.1 is 0.00028 in the African population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.00008) for BS1, and therefore meets this criterion (BS1). The c.1245T>C (p.His415His) variant is found in a patient with an alternate molecular basis of disease (Internal database - Invitae) (BP5). The silent c.1245T>C (p.His415His) variant is not predicted to affect splicing using multiple computational tools and does not affect a highly conserved nucleotide (BP4, BP7). In summary the c.1245T>C (p.His415His) variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS1, BP5, BP4, BP7). (TCF4 Specifications v.3; approval date 6/25/2024)
Eurofins Ntd Llc (ga)	RCV000724844	SCV000226241	uncertain significance	not provided	2015-05-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000174858	SCV000514870	likely benign	not specified	2015-10-19	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV002390426	SCV002675179	likely benign	Inborn genetic diseases	2017-09-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517681	SCV003504129	likely benign	Pitt-Hopkins syndrome	2024-11-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003895184	SCV004712665	likely benign	TCF4-related disorder	2022-06-20	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).