Submissions for variant NM_001083962.2(TCF4):c.991-6T>G

gnomAD frequency: 0.00005  dbSNP: rs201721676

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000523429	SCV000621946	uncertain significance	not provided	2017-10-31	criteria provided, single submitter	clinical testing	The c.991-6 T>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. This variant is observed in 6/23948 (0.03%) alleles from individuals of African background, in large population cohorts (Lek et al., 2016). Several in-silico splice prediction models predict that c.991-6 T>G damages or destroys the splice acceptor site in intron 12, which may lead to abnormal gene splicing. However, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. Therefore, based on the currentlyavailable information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000797687	SCV000937261	uncertain significance	Pitt-Hopkins syndrome	2020-07-31	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 of the TCF4 gene. It does not directly change the encoded amino acid sequence of the TCF4 protein. This variant is present in population databases (rs201721676, ExAC 0.06%). This variant has not been reported in the literature in individuals with TCF4-related disease. ClinVar contains an entry for this variant (Variation ID: 453087). 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. 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.