Submissions for variant NM_000548.5(TSC2):c.2090dup (p.Leu697fs) (rs137854189)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000497886	SCV000589552	pathogenic	not provided	2017-06-20	criteria provided, single submitter	clinical testing	The c.2090dupT pathogenic variant in the TSC2 gene has been reported previously in an individual with a clinical diagnosis of TSC (Rendtorff et al., 2005). The duplication causes a frameshift starting with codon Leucine 697, changes this amino acid to a Phenylalanine residue and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Leu697PhefsX6. This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Furthermore, the c.2090dupT variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). Therefore, the presence of c.2090dupT is consistent with a diagnosis of TSC in this individual.
Invitae	RCV001038792	SCV001202286	pathogenic	Tuberous sclerosis 2	2019-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu697Phefs*6) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with tuberous sclerosis complex (PMID: 16114042). ClinVar contains an entry for this variant (Variation ID: 49650). Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). For these reasons, this variant has been classified as Pathogenic.
Tuberous sclerosis database (TSC2)	RCV000042912	SCV000066708	not provided	Tuberous sclerosis syndrome		no assertion provided	curation