Submissions for variant NM_000548.5(TSC2):c.1257+20G>A

gnomAD frequency: 0.00001  dbSNP: rs1436234038

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000521794	SCV000621072	uncertain significance	not provided	2017-09-22	criteria provided, single submitter	clinical testing	A variant of uncertain significance has been identified in the TSC2 gene. The c.1257+20 G>A variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.1257+20 G>A variant is not observed in large population cohorts (Lek et al., 2016). Several in-silico splice prediction models predict that c.1257+20 G>A creates a cryptic donor site which may supplant the natural donor site 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	RCV001858024	SCV002117018	uncertain significance	Tuberous sclerosis 2	2022-11-08	criteria provided, single submitter	clinical testing	This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change falls in intron 12 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 452279). This variant has not been reported in the literature in individuals affected with TSC2-related conditions.