Submissions for variant NM_000548.5(TSC2):c.848+281C>T

dbSNP: rs45517132

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000457139	SCV000544426	pathogenic	Tuberous sclerosis 2	2022-05-03	criteria provided, single submitter	clinical testing	Studies have shown that this variant results in a splicing defect and introduces a premature termination codon (PMID: 10533066, 11068191). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 49923). This variant is also known as IVS8+281C>T. This variant has been observed in individual(s) with tuberous sclerosis complex (TSC) (PMID: 10533066, 26540169; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 9 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197516	SCV001368292	pathogenic	Lymphangiomyomatosis	2018-12-21	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PM2,PS1.
Centogene AG - the Rare Disease Company	RCV000457139	SCV001426479	pathogenic	Tuberous sclerosis 2		criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000457139	SCV002040924	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV002243690	SCV002512895	pathogenic	not provided	2021-07-23	criteria provided, single submitter	clinical testing	Non-canonical splice site variant demonstrated to result in loss-of-function; RNA studies indicate the variant activates a cryptic splice donor site in intron 9, leading to the addition of incorrect amino acids and an additional stop codon in exon 10 (Mayer et al., 1999; Mayer et al., 2000); In silico analysis supports a deleterious effect on splicing; No data available from ethnically-matched control populations to assess the frequency of this variant; This variant is associated with the following publications: (PMID: 19823873, 10533066, 11068191, 32860008, 26540169)
Ambry Genetics	RCV002444498	SCV002680816	pathogenic	Hereditary cancer-predisposing syndrome	2019-12-20	criteria provided, single submitter	clinical testing	The c.848+281C>T intronic pathogenic mutation results from a C to T substitution 281 nucleotides after coding exon 8 in the TSC2 gene. This mutation has been detected twice, once as a de novo occurrence, in individuals meeting diagnostic criteria for tuberous sclerosis complex (TSC) (Mayer K et al. Hum. Mutat., 1999;14:401-11; Tyburczy ME et al. PLoS Genet., 2015 Nov;11:e1005637). Functional studies performed at the RNA level showed this mutation creates a cryptic splice donor site that leads to the structural functionality of intron 8, resulting in the incorporation of a pseudoexon between exons 8 and 9, and ultimately resulting in a frameshift and premature protein truncation (Mayer K et al. Biochim. Biophys. Acta, 2000 Nov;1502:495-507). Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to create a new alternate splice donor site; however, direct evidence is unavailable. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Tuberous sclerosis database (TSC2)	RCV000043190	SCV000066991	not provided	Tuberous sclerosis syndrome		no assertion provided	curation