Submissions for variant NM_001083962.2(TCF4):c.1876C>T (p.Arg626Ter)

dbSNP: rs1131691735

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000493014	SCV000582727	pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 46 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); This variant is associated with the following publications: (PMID: 22045651, 22460224, 29604340, 31440721)
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000660298	SCV000782335	likely pathogenic	Pitt-Hopkins syndrome	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000660298	SCV000819174	pathogenic	Pitt-Hopkins syndrome	2022-09-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 430016). This premature translational stop signal has been observed in individual(s) with Pitt–Hopkins Syndrome (PMID: 22045651). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg626*) in the TCF4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TCF4 are known to be pathogenic (PMID: 18728071, 22045651).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000493014	SCV001446521	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000660298	SCV002762860	pathogenic	Pitt-Hopkins syndrome	2020-12-23	criteria provided, single submitter	research	A heterozygous nonsense variation in exon 19 of the TCF4 gene that results in a stop codon and premature truncation of the protein at codon 728 was detected. The observed variant c.2182C>T (p.Arg728Ter) has not been reported in the 1000 genomes and gnomAD databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. Segregation analysis showed this variant to be de novo. In summary, the variant meets our criteria to be classified as a pathogenic variant.
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000660298	SCV003035475	pathogenic	Pitt-Hopkins syndrome	2022-04-05	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003159600	SCV003882800	pathogenic	Inborn genetic diseases	2023-02-14	criteria provided, single submitter	clinical testing	The c.1876C>T (p.R626*) alteration, located in exon 18 (coding exon 17) of the TCF4 gene, consists of a C to T substitution at nucleotide position 1876. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 626. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in multiple individuals with clinical features of Pitt-Hopkins syndrome (Liu, 2018; Whalen, 2012). Based on the available evidence, this alteration is classified as pathogenic.