Submissions for variant NM_001083962.2(TCF4):c.1916_1917del (p.Arg639fs)

dbSNP: rs1555708227

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV001507066	SCV001712038	likely pathogenic	Pitt-Hopkins syndrome	2021-04-02	reviewed by expert panel	curation	The p.R639KfsX71 variant in TCF4 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a TCF4 where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the TCF4 is pathogenic (PVS1). The p.R639KfsX71 variant in TCF4 is absent from gnomAD (PM2_Supporting). In summary, the p.R639KfsX71 variant in TCF4 is classified as likely pathogenic based on the ACMG/AMP criteria (PVS1, PM2_supporting).
GeneDx	RCV000627504	SCV000748504	likely pathogenic	not provided	2018-03-15	criteria provided, single submitter	clinical testing	The c.1916_1917delGA variant in the TCF4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.1916_1917delGA variant causes a frameshift starting with codon Arginine 639, changes this amino acid to a Lysine residue, and creates a premature Stop codon at position 71 of the new reading frame, denoted p.Arg639LysfsX71. This frameshift variant replaces the typical last 33 amino acid residues in the TCF4 protein with 70 different amino acid residues. This alteration may interfere with the proper formation and/or function of the TCF4 protein. The c.1916_1917delGA variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1916_1917delGA as a likely pathogenic variant.