ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.139-2A>G

dbSNP: rs2084954667
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001069910 SCV001235108 pathogenic Tuberous sclerosis 2 2022-11-08 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 2 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 individuals with renal cell carcinoma and colon cancer who had features consistent with Cowden syndrome and tuberous sclerosis (PMID: 24271014, 29684080; Invitae). ClinVar contains an entry for this variant (Variation ID: 863043). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Neuberg Centre For Genomic Medicine, NCGM RCV001069910 SCV005042958 pathogenic Tuberous sclerosis 2 criteria provided, single submitter clinical testing The invariant splice acceptor c.139-2A>G variant in TSC2 gene has been reported in an individual affected with TSC2-related disorders Yehia et al., 2018. The c.139-2A>G variant is novel not in any individuals in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic. Loss of function variants have been previously reported to be disease causing. However, additional functional studies will be required to prove the pathogenicity of this variant. For these reasons, this variant has been classified as Likely Pathogenic.

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