Submissions for variant NM_001083962.2(TCF4):c.1147-3C>G

dbSNP: rs2056333687

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001174968	SCV001338450	uncertain significance	not specified	2020-04-06	criteria provided, single submitter	clinical testing	Variant summary: TCF4 c.1147-3C>G alters a conserved nucleotide located close to a canonical splice site 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 3' acceptor site, and two predict the variant creates a 3' acceptor site 2 nucleotides upstream from the original, canonical splice site; that would result in a frameshift at the protein level. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 226208 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1147-3C>G in individuals affected with Pitt-Hopkins syndrome and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001209903	SCV001381359	uncertain significance	Pitt-Hopkins syndrome	2020-01-21	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with TCF4-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 14 of the TCF4 gene. It does not directly change the encoded amino acid sequence of the TCF4 protein, but it affects a nucleotide within the consensus splice site of the intron.