Submissions for variant NM_000548.5(TSC2):c.226-1G>A

dbSNP: rs397515134

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001379463	SCV001577266	likely pathogenic	Tuberous sclerosis 2	2022-10-04	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with clinical features of TSC2-related conditions (PMID: 21520333). 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. 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: 65180). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 3 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).
PreventionGenetics, part of Exact Sciences	RCV004537243	SCV004121085	pathogenic	TSC2-related disorder	2022-10-25	criteria provided, single submitter	clinical testing	The TSC2 c.226-1G>A variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/65180/). Variants that disrupt the consensus splice acceptor site in TSC2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Ambry Genetics	RCV004018982	SCV005036297	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-05	criteria provided, single submitter	clinical testing	The c.226-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 3 of the TSC2 gene. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TSC-related disease (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV005429221	SCV006100395	likely pathogenic	not provided	2024-12-16	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; Also known as IVS2+1G>A; This variant is associated with the following publications: (PMID: 18466115, 21520333)
Tuberous sclerosis database (TSC2)	RCV000055397	SCV000083618	not provided	Tuberous sclerosis syndrome		no assertion provided	curation