ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2355G>A (p.Gln785=)

dbSNP: rs2088708544
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001036320 SCV001199675 uncertain significance Tuberous sclerosis 2 2021-07-04 criteria provided, single submitter clinical testing Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has been observed to segregate with tuberous sclerosis complex in a family in the Leiden Open-source Variation Database (PMID: 21520333). This variant is not present in population databases (ExAC no frequency). This sequence change affects codon 785 of the TSC2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the TSC2 protein. This variant also falls at the last nucleotide of exon 21 of the TSC2 coding sequence, which is part of the consensus splice site for this exon.
Mayo Clinic Laboratories, Mayo Clinic RCV001509506 SCV001716254 uncertain significance not provided 2020-12-08 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001036320 SCV002040693 uncertain significance Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001509506 SCV004221416 likely pathogenic not provided 2021-08-13 criteria provided, single submitter clinical testing This synonymous variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with tuberous sclerosis complex (TSC) (PMID: 34403804 (2021), 35918040 (2022)). Internal laboratory data indicates this variant appears to segregate with disease in at least one family. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper TSC2 mRNA splicing. Based on the available information, this variant is classified as likely pathogenic.

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