Submissions for variant NM_001083962.2(TCF4):c.413C>G (p.Thr138Ser)

dbSNP: rs796053416

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV002517021	SCV004176285	likely benign	Pitt-Hopkins syndrome	2023-12-06	reviewed by expert panel	curation	The p.Thr138Ser variant in TCF4 is absent from gnomAD (PM2_Supporting). The p.Thr138Ser variant is observed in at least 3 unaffected individuals (internal database - GeneDx) (BS2). Computational analysis prediction tools suggest that the p.Thr138Ser variant does not have a deleterious impact; however this information does not predict clinical significance on its own (BP4). In the absence of other pathogenic evidence beyond PM2_Supporting, and because this variant has been observed in 3 unaffected individuals, the ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel has agreed to overrule the PM2_Supporting criterion. In summary, the p.Thr138Ser variant in TCF4 is classified as likely benign based on the ACMG/AMP criteria (BS2, BP4).
GeneDx	RCV000189720	SCV000243368	likely benign	not specified	2016-04-07	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	RCV002314769	SCV000849270	uncertain significance	Inborn genetic diseases	2017-03-31	criteria provided, single submitter	clinical testing	The p.T138S variant (also known as c.413C>G), located in coding exon 6 of the TCF4 gene, results from a C to G substitution at nucleotide position 413. The threonine at codon 138 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517021	SCV003283454	uncertain significance	Pitt-Hopkins syndrome	2022-07-06	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 138 of the TCF4 protein (p.Thr138Ser). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TCF4-related conditions. ClinVar contains an entry for this variant (Variation ID: 207532). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.