Submissions for variant NC_000016.9:g.(?_2110665)_(2113060_?)del

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001378862	SCV001576543	likely pathogenic	Tuberous sclerosis 2	2016-12-20	criteria provided, single submitter	clinical testing	In summary, this is an in-frame deletion that disrupts an important amino acid residue and protein functional domain. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is a gross deletion of the genomic region encompassing exons 11-15 of the TSC2 gene. This leads to an in-frame deletion, preserving the integrity of the reading frame. Deletions of exons 11-15 have not been reported in the literature in individuals with a TSC-related disease. This in-frame deletion (p.Ala326_Lys533del) is expected to completely remove a predicted coiled-coil domain (residues 346-371) within the TSC1 binding domain (T1BD), which is important for proper TSC2 protein function (PMID: 18466115, 11741833, 9580671). Smaller in-frame deletions including p.Ser428del and deletion of exon 11 (also known as exon 10) have been reported in individuals affected with tuberous sclerosis complex, and have been determined to be pathogenic (PMID: 17287951, 11112665, 17304050, 22867869, 21520333), suggesting that this larger deletion may also be deleterious to protein function.