Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV003512070 | SCV004248013 | uncertain significance | Tuberous sclerosis 2 | 2023-11-17 | criteria provided, single submitter | clinical testing | This sequence change creates a premature translational stop signal (p.Leu957Phefs*3) in the TSC2 gene. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). However, tissue-specific alternative splicing of TSC2 gene results in a functional isoform lacking in-frame exon 26 (also known as exon 25, PMID: 26703369). For this reason the clinical significance of loss of function variants in exon 26 is currently uncertain. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with chronic kidney disease (PMID: 30586318). ClinVar contains an entry for this variant (Variation ID: 562247). 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 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. |
| Gharavi Laboratory, |
RCV000681682 | SCV000809129 | likely pathogenic | not provided | 2018-09-16 | no assertion criteria provided | research | |
| Prevention |
RCV004723060 | SCV005338792 | uncertain significance | TSC2-related disorder | 2024-06-27 | no assertion criteria provided | clinical testing | The TSC2 c.2870dupT variant is predicted to result in a frameshift and premature protein termination (p.Leu957Phefs*3). This variant has been identified in one individual with chronic kidney disease (Groopman et al. 2019. PubMed ID: 30586318). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants are expected to result in loss of function; however, it has been demonstrated that tissue-specific alternative splicing of the TSC2 gene results in a functional isoform that lacks exon 26 which is in-frame (also known as exon 25) (Ekong et al. 2016. PubMed ID: 26703369). This variant is classified as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/562247/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |