ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2221-1G>A

dbSNP: rs45517218
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482093 SCV000567231 pathogenic not provided 2015-07-16 criteria provided, single submitter clinical testing The c.2221-1 G>A splice site variant in the TSC2 gene destroys the canonical splice acceptor site inintron 20. It is predicted to cause abnormal gene splicing, either leading to an abnormal message that issubject to nonsense-mediated mRNA decay, or to an abnormal protein product if the message is used forprotein translation. A different nucleotide substitution at the same position (c.2221-1 G>C) has beenpreviously reported in association with tuberous sclerosis (TSC2 LOVD; Stenson et al., 2014).Additionally, c.2221-1 G>A was not observed in approximately 6,500 individuals of European and AfricanAmerican ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variantin these populations. Therefore, we interpret the c.2221-1 G>A variant as pathogenic.
Athena Diagnostics RCV000482093 SCV000615891 pathogenic not provided 2016-07-25 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001797734 SCV002040950 pathogenic Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001797734 SCV002206568 pathogenic Tuberous sclerosis 2 2021-07-09 criteria provided, single submitter clinical testing This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 20 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). Disruption of this splice site has been observed in individual(s) with tuberous sclerosis complex (PMID: 29196670). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 419433).

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