Submissions for variant NM_001083962.2(TCF4):c.341G>A (p.Arg114Lys)

gnomAD frequency: 0.00043  dbSNP: rs139876825

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	RCV001087507	SCV005440653	benign	Pitt-Hopkins syndrome	2024-06-25	reviewed by expert panel	curation	The highest population minor allele frequency of the p.Arg114Lys variant in TCF4 in gnomAD v4.1 is 0.0018 in the African population, which is higher than the ClinGen Rett and Angelman-like Disorders VCEP threshold (≥0.0003) for BA1, and therefore meets this criterion (BA1). The p.Arg114Lys variant is observed in at least 2 unaffected individuals (Internal database - Ambry) (BS2). In summary, the p.Arg114Lys variant in TCF4 is classified as a benign variant based on the ACMG/AMP criteria (BA1, BS2). (TCF4 Specifications v.3; approved on 6/25/2024)
Eurofins Ntd Llc (ga)	RCV000154002	SCV000203627	uncertain significance	not provided	2015-11-11	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002312686	SCV000847110	likely benign	Inborn genetic diseases	2024-11-15	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.
GeneDx	RCV000154002	SCV000979199	benign	not provided	2019-10-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001087507	SCV001003943	likely benign	Pitt-Hopkins syndrome	2024-12-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739481	SCV005345470	likely benign	TCF4-related disorder	2024-06-26	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).