Submissions for variant NM_001083962.2(TCF4):c.2010_2011del (p.Gln670fs)

dbSNP: rs796053429

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	RCV001507033	SCV001711980	likely pathogenic	Pitt-Hopkins syndrome	2021-04-02	reviewed by expert panel	curation	The p.Q670HfsX40 variant in TCF4 is predicted to cause a premature stop codon that leads to a truncated or absent protein in a gene where loss-of-function is an established mechanism. There is significant evidence that loss of this region of the gene is pathogenic (PVS1). The p.Q670HfsX40 variant in TCF4 is absent from gnomAD (PM2_Supporting). In summary, the p.Q670HfsX40 variant in TCF4 is classified as likely pathogenic based on the ACMG/AMP criteria (PVS1, PM2_supporting).
GeneDx	RCV000189734	SCV000243382	likely pathogenic	not provided	2017-02-16	criteria provided, single submitter	clinical testing	The c.2010_2011delGA variant in the TCF4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.2010_2011delGA variant in the TCF4 gene variant causes a frameshift starting with codon Glutamine 670, changes this amino acid to a Histidine residue, and creates a premature Stop codon at position 40 of the new reading frame, denoted p.Gln670HisfsX40. This frameshift variant replaces the typical last two amino acid residues in the TCF4 protein with 39 incorrect amino acid residues. This change is expected to alter the normal structure and function of the resultant protein. The c.2010_2011delGA variant in the TCF4 gene variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.2010_2011delGA variant in the TCF4 gene as a likely pathogenic variant.