Submissions for variant NM_000548.5(TSC2):c.3693_3696del (p.Ser1232fs)

dbSNP: rs137853993

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000489018	SCV000577131	pathogenic	not provided	2022-12-19	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16981987, 17304050, 21510812, 15798777, 35918040, 31018109, 29476190, 29500070, 33376960, 23217510)
Athena Diagnostics Inc	RCV000489018	SCV001146282	pathogenic	not provided	2019-08-12	criteria provided, single submitter	clinical testing	The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one symptomatic patient, and not found in general population data.
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV001194684	SCV001364430	pathogenic	Tuberous sclerosis 2	2022-07-17	criteria provided, single submitter	clinical testing
Invitae	RCV001194684	SCV001417486	pathogenic	Tuberous sclerosis 2	2022-12-10	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 50013). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 16981987, 29500070). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser1232Thrfs*92) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050).
Genome-Nilou Lab	RCV001194684	SCV002040981	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496682	SCV002780734	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2022-03-19	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002496682	SCV003924177	pathogenic	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-03-30	criteria provided, single submitter	clinical testing	TSC2 NM_000548.4 exon 31 p.Ser1232Thrfs*92 (c.3693_3696del): This variant has been reported in the literature in several individuals with tuberous sclerosis (Hung 2006 PMID:16981987, Au 2007 PMID:17304050, Lyall 2012 PMID:23217510, Papadopoulou 2018 PMID:29500070), including several entries in the Tuberous Sclerosis Database (http://chromium.lovd.nl/LOVD2/TSC/variants). This variant is not present in large control databases but is present in ClinVar (Variation ID:50013). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 92 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Rosset 2017 PMID:28222202). In summary, this variant is classified as pathogenic based on the data above (impact to protein, absence from controls, etc.).
Tuberous sclerosis database (TSC2)	RCV000043281	SCV000067083	not provided	Tuberous sclerosis syndrome		no assertion provided	curation