Submissions for variant NM_000548.5(TSC2):c.775-2A>G

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
3billion, Medical Genetics	RCV002283848	SCV002572979	likely pathogenic	Tuberous sclerosis 2	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Canonical splice site is predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
Ambry Genetics	RCV002409634	SCV002672177	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-08-16	criteria provided, single submitter	clinical testing	The c.775-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 8 in the TSC2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the ESEfinder splice site prediction tool, this alteration is predicted to abolish the native splice acceptor site. Using the Human Splicing Finder (HSF) splice site prediction tool, this alteration is predicted to weaken, but not abolish, the native splice acceptor site; however, direct evidence is unavailable (Desmet FO et al. Nucleic Acids Res. 2009 May;37:e67). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic
Labcorp Genetics (formerly Invitae), Labcorp	RCV002283848	SCV005756728	likely pathogenic	Tuberous sclerosis 2	2024-06-08	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the TSC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1705534). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.