Submissions for variant NM_000548.5(TSC2):c.2838-3T>G

dbSNP: rs553942147

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480205	SCV000573771	uncertain significance	not provided	2017-03-10	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TSC2 gene. The c.2838-3 T>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.2838-3 T>G variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). An in-silico splice prediction model predicts that c.2838-3 T>G may destroy the natural acceptor site of intron 25 and 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 currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Invitae	RCV000695827	SCV000824348	uncertain significance	Tuberous sclerosis 2	2021-07-31	criteria provided, single submitter	clinical testing	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. 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. This variant has not been reported in the literature in individuals with TSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 424000). This variant is not present in population databases (ExAC no frequency). This sequence change falls in intron 25 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein, but it affects a nucleotide within the consensus splice site of the intron.
Genome-Nilou Lab	RCV000695827	SCV002040725	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002438186	SCV002750467	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-16	criteria provided, single submitter	clinical testing	The c.2838-3T>G intronic variant results from a T to G substitution 3 nucleotides upstream from coding exon 25 in the TSC2 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. However, this alteration occurs at the splice acceptor site for an exon that is absent in biologically relevant transcripts (Ekong R et al. Hum. Mutat. 2016 Apr; 37:362-70). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.