Submissions for variant NM_000368.5(TSC1):c.2975+1G>A

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV003123155	SCV003798774	uncertain significance	not provided	2022-08-05	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18466115)
Ambry Genetics	RCV003294635	SCV003997238	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-04	criteria provided, single submitter	clinical testing	The c.2975+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 20 of the TSC1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in a transcript predicted to lead to a protein with an in-frame deletion of 54 amino acids; however, the exact functional impact of the deleted amino acids is unknown at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003459781	SCV004204485	uncertain significance	Isolated focal cortical dysplasia type II	2023-05-24	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV003778666	SCV004648581	uncertain significance	Tuberous sclerosis 1	2024-02-21	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 22 of the TSC1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TSC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2428914). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that disruption of this splice site results in skipping of exon 22, but is expected to preserve the integrity of the reading-frame (Invitae). 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.