Submissions for variant NM_001083962.2(TCF4):c.990G>A (p.Ser330=)

dbSNP: rs587784469

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Rett and Angelman-like Disorders Variant Curation Expert Panel	RCV000147730	SCV001712000	pathogenic	Pitt-Hopkins syndrome	2024-02-23	reviewed by expert panel	curation	The p.Ser330= variant in TCF4 is absent from gnomAD v4 (PM2_supporting). Splice prediction analysis using multiple computational tools suggests an impact to splicing (PP3). The p.Ser330= variant has been observed in at least 2 individuals with intellectual disability/autism (PMIDs: 29695756, 25693842) (PS4_supporting). The p.Ser330= variant in TCF4 has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with intellectual disability (PMID: 25693842, internal database -Invitae) (PM6). The p.Ser330= variant in TCF4 has been reported as a de novo occurrence (biological parentage confirmed) in at least 3 individuals with intellectual disability/autism (PMIDs: 29695756, 29158550, 31785789, 1981491, 33767182, internal database - Invitae) (PS2_very strong). In summary, the p.Ser330= variant in TCF4 is classified as pathogenic for Pitt-Hopkins syndrome based on the ACMG/AMP criteria (PM2_supporting, PP3, PS4_supporting, PM6, PS2_very strong).
Genetic Services Laboratory, University of Chicago	RCV000147730	SCV000195195	likely pathogenic	Pitt-Hopkins syndrome	2014-02-20	criteria provided, single submitter	clinical testing
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	RCV000147730	SCV000586709	pathogenic	Pitt-Hopkins syndrome	2017-08-01	criteria provided, single submitter	clinical testing	De novo variant at the last nucleotide position in gxon 13 of the TCF4 gene in a patient with hypotonia and developmental delay. This Variant has been previously reported as de novo (PMID22495309) in a patient with ID. In house splicing assays showed aberrant splicing. The variant is thus scored as pathogenic (ACMG class 5).
GeneDx	RCV000521305	SCV000616931	pathogenic	not provided	2022-08-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 25693842, 29695756, 33767182, 28191890, 22495309, 25780760, 32579932, 27694994, 31785789, 29158550, 32369273, 31069529, 31981491)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000147730	SCV003844864	pathogenic	Pitt-Hopkins syndrome	2023-02-16	criteria provided, single submitter	clinical testing	Variant summary: TCF4 c.990G>A (p.Ser330Ser) alters the non-conserved last nucleotide of exon 12 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site. One submitter via Clinvar stated that an in house splicing assay showed aberrant splicing, however did not provide supporting data (Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universitt Erlangen-Nrnberg). The variant was absent in 250940 control chromosomes. c.990G>A has been reported in the literature in individuals affected with Pitt-Hopkins Syndrome, autism spectrum disorder, intellectual disabilities, and neurodevelopmental disorders, including multiple affected individuals in which the variant was de novo (e.g., Geoffrey_2015, Tan_2016, Popp_2017, Mary_2018, Turner_2019, Satterstrom_2020, Martinez-Granero_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported in the literature. Three ClinVar submitters (evaluation after 2014) have cited the variant, and all laboratories classified the variant as pathogenic (n = 2) or likely pathogenic (n = 1). Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000521305	SCV004010982	likely pathogenic	not provided	2023-04-01	criteria provided, single submitter	clinical testing	TCF4: PS2, PM2:Supporting, PP3, PS4:Supporting
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000521305	SCV004026398	pathogenic	not provided	2023-05-19	criteria provided, single submitter	clinical testing	PS4, PP3, PM2_SUP