Submissions for variant NM_000368.5(TSC1):c.2208+2T>A

dbSNP: rs1064794132

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487211	SCV000567931	pathogenic	not provided	2015-09-16	criteria provided, single submitter	clinical testing	The c.2208+2T>A variant in the TSC1 gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. This splice site variant destroys the canonical splice donor site in intron 17. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used for protein translation. The c.2208+2T>A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2208+2T>A as a pathogenic variant.
Ambry Genetics	RCV000565398	SCV000664763	pathogenic	Hereditary cancer-predisposing syndrome	2018-10-12	criteria provided, single submitter	clinical testing	The c.2208+2T>A intronic pathogenic mutation results from a T to A substitution two nucleotides after coding exon 15 in the TSC1 gene. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781918	SCV000920329	likely pathogenic	Tuberous sclerosis syndrome	2018-03-06	criteria provided, single submitter	clinical testing	Variant summary: TSC1 c.2208+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was absent in 245912 control chromosomes. To our knowledge, no occurrence of c.2208+2T>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics	RCV001333394	SCV001525955	likely pathogenic	Tuberous sclerosis 1	2018-04-03	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV001333394	SCV002040831	pathogenic	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004568170	SCV005054410	likely pathogenic	Isolated focal cortical dysplasia type II	2024-01-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001333394	SCV005083603	likely pathogenic	Tuberous sclerosis 1	2024-04-12	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.