Submissions for variant NM_000548.5(TSC2):c.4089CTC[1] (p.Ser1365del)

dbSNP: rs755101865

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704621	SCV000833577	uncertain significance	Tuberous sclerosis 2	2024-11-21	criteria provided, single submitter	clinical testing	This variant, c.4092_4094del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Ser1365del), but otherwise preserves the integrity of the reading frame. 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: 580940). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
GeneDx	RCV001574252	SCV001801041	uncertain significance	not provided	2019-10-29	criteria provided, single submitter	clinical testing	In-frame deletion of one amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect
Sema4, Sema4	RCV002256487	SCV002533500	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-01	criteria provided, single submitter	curation
Ambry Genetics	RCV002256487	SCV002629313	uncertain significance	Hereditary cancer-predisposing syndrome	2024-09-25	criteria provided, single submitter	clinical testing	The c.4092_4094delCTC variant (also known as p.S1365del) is located in coding exon 33 of the TSC2 gene. This variant results from an in-frame CTC deletion at nucleotide positions 4092 to 4094. This results in the in-frame deletion of a serine at codon 1365. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear.
PreventionGenetics, part of Exact Sciences	RCV004535751	SCV004121395	uncertain significance	TSC2-related disorder	2022-11-23	criteria provided, single submitter	clinical testing	The TSC2 c.4092_4094delCTC variant is predicted to result in an in-frame deletion (p.Ser1365del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-2134311-TCTC-T). It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/580940/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004802397	SCV005428324	uncertain significance	Tuberous sclerosis syndrome	2024-07-10	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid of the TSC2 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC2-related disorders in the literature. This variant has been identified in 1/248248 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.