Submissions for variant NM_000548.5(TSC2):c.136_138+1del

dbSNP: rs137854117

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000546941	SCV000644234	pathogenic	Tuberous sclerosis 2	2017-06-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the TSC2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TSC2-related disease. 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. A different deletion affecting 2 of these nucleotides (c.138_138+1del) has been determined to be pathogenic (PMID: 15595939, 25782670). This suggests that these nucleotides are important for normal RNA splicing, and that other variants at this position may also be pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). For these reasons, this variant has been classified as Pathogenic.