Submissions for variant NM_000548.5(TSC2):c.1283_1285del (p.Ser428del)

dbSNP: rs137853983

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000190056	SCV000243731	pathogenic	not provided	2023-04-18	criteria provided, single submitter	clinical testing	Reported in multiple unrelated individuals with a clinical diagnosis of TSC, including as an assumed de novo variant in two individuals with TSC (Au et al., 2007; van Eeghen et al., 2013; TSC2 LOVD); Published functional studies demonstrate a damaging effect on TSC complex formation and TSC complex dependent inhibition of mTORC1 activity (Rosengren et al., 2020; TSC2 LOVD); Not observed at significant frequency in large population cohorts (gnomAD); In-frame deletion of a single amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17304050, 21520333, 32917966, 32555378, 22867869, LOVD)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000475301	SCV000544460	likely pathogenic	Tuberous sclerosis 2	2023-06-15	criteria provided, single submitter	clinical testing	This variant has been observed in individuals with clinical features of tuberous sclerosis complex (PMID: 17304050, 21520333, 22867869, 32555378; Invitae). This variant is not present in population databases (gnomAD no frequency). This variant, c.1283_1285del, results in the deletion of 1 amino acid(s) of the TSC2 protein (p.Ser428del), but otherwise preserves the integrity of the reading frame. ClinVar contains an entry for this variant (Variation ID: 49644). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies have shown that this variant affects TSC2 function (PMID: 32555378). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000190056	SCV001471649	likely pathogenic	not provided	2020-08-27	criteria provided, single submitter	clinical testing	The TSC2 c.1283_1285del, p.Ser428del variant (rs137853983; ClinVar Variation ID: 49644), has been previously published following identification in at least three individuals included in screening cohorts for TSC2-related clinical presentations (Au 2007, Rosengren 2020, van Eeghen 2013). Functional evaluation in heterologous cell culture indicates this variant disrupts TSC complex activity as measured by increased downstream mTOR activity (Rosengren 2020). This variant is also absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. Based on the available information, the p.Ser428del variant is considered likely pathogenic. References: Au KS et al. Genotype/phenotype correlation in 325 individuals referred for a diagnosis of tuberous sclerosis complex in the United States. Genet Med. 2007 Feb;9(2):88-100. Rosengren et al. Mutational analysis of TSC1 and TSC2 in Danish patients with tuberous sclerosis complex. Sci Rep. 2020 Jun 18;10(1):9909. van Eeghen AM et al. Central TSC2 missense mutations are associated with a reduced risk of infantile spasms. Epilepsy Res. 2013 Jan;103(1):83-7.
PreventionGenetics, part of Exact Sciences	RCV004537172	SCV004116495	likely pathogenic	TSC2-related disorder	2023-03-06	criteria provided, single submitter	clinical testing	The TSC2 c.1283_1285delCCT variant is predicted to result in an in-frame deletion (p.Ser428del). This variant was reported in four individuals with suspected tuberous sclerosis complex (TSC; Supplement, Au et al. 2007. PubMed ID: 17304050; Table S1, van Eeghen et al. 2012. PubMed ID: 22867869; Table 2, Rosengren et al. 2020. PubMed ID: 32555378; Table S1, Referred to as TSC2:p.427_428del, Meng et al. 2021. PubMed ID: 32917966). In one of these individuals this variant was reported as a low level mosaic finding (Read Frequency of 8%; Table 2, Rosengren et al. 2020. PubMed ID: 32555378). In another one of these individuals, the variant was maternally inherited and the TSC diagnosis was uncertain (Table S1, Referred to as TSC2:p.427_428del, Meng et al. 2021. PubMed ID: 32917966). This variant has been reported in multiple probands in the Leiden Open Database, several of whom inherited the variant (https://databases.lovd.nl/shared/view/TSC2?search_VariantOnGenome%2FDBID=%3D%22TSC2_000813%22). This variant has been reported in three additional unrelated individuals undergoing TSC genetic testing with clinical features consistent with TSC (PreventionGenetics LLC, Internal Data). In vitro functional studies suggest this variant leads to disrupted TSC-complex function (Figure 2, Table 3, Rosengren et al. 2020. PubMed ID: 32555378). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as pathogenic and likely pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/49644/). This variant is interpreted as likely pathogenic.
Tuberous sclerosis database (TSC2)	RCV000042906	SCV000066702	not provided	Tuberous sclerosis syndrome		no assertion provided	curation