Submissions for variant NM_001083962.2(TCF4):c.1726C>T (p.Arg576Ter)

dbSNP: rs1555710726

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000578535	SCV000680956	pathogenic	not provided	2023-03-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27179618, 25780760, 29695756, 31428121, 31981491, 33644862)
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000824831	SCV000965721	likely pathogenic	Pitt-Hopkins syndrome	2015-01-01	criteria provided, single submitter	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV000578535	SCV001449658	pathogenic	not provided	2016-11-28	criteria provided, single submitter	clinical testing
3billion	RCV000824831	SCV002012279	pathogenic	Pitt-Hopkins syndrome	2021-10-02	criteria provided, single submitter	clinical testing	Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is not observed in the gnomAD v2.1.1 dataset (PM2). The variant has been reported as pathogenic (ClinVar ID: VCV000488988.5). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Invitae	RCV000824831	SCV002228644	pathogenic	Pitt-Hopkins syndrome	2023-06-05	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: 488988). This variant is also known as p.Arg678*. This premature translational stop signal has been observed in individual(s) with clinical features of Pitt-Hopkins syndrome (PMID: 27179618, 29695756, 31428121). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg576*) 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).
Genetics and Molecular Pathology, SA Pathology	RCV000824831	SCV002556556	pathogenic	Pitt-Hopkins syndrome	2021-06-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002413657	SCV002716667	pathogenic	Inborn genetic diseases	2017-06-22	criteria provided, single submitter	clinical testing	The p.R576* pathogenic mutation (also known as c.1726C>T), located in coding exon 17 of the TCF4 gene, results from a C to T substitution at nucleotide position 1726. This changes the amino acid from an arginine to a stop codon within coding exon 17. In one study, an individual with Pitt Hopkins Syndrome features who carried this mutation was used as an affected control (Maduro V et al. Orphanet J Rare Dis, 2016 May;11:62). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Revvity Omics, Revvity	RCV000578535	SCV003827973	pathogenic	not provided	2022-05-06	criteria provided, single submitter	clinical testing