ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.225+1G>A

dbSNP: rs1567387207
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768348 SCV000899046 likely pathogenic Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2 2021-11-23 criteria provided, single submitter clinical testing TSC2 NM_000548.4 exon 3 c.225+1G>A: This variant has not been reported in the literature and is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant alters the consensus splice sequence (+/- 1,2) which is predicted to result 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, data on this variant is highly suspicious for disease, but requires further evidence for pathogenicity. Therefore, this variant classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp RCV001378178 SCV001575689 likely pathogenic Tuberous sclerosis 2 2024-11-04 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 3 of the TSC2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with clinical features of TSC2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 626196). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
3billion RCV001378178 SCV003841729 pathogenic Tuberous sclerosis 2 2023-02-23 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000626196). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

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