ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1283_1285del (p.Ser428del) (rs137853983)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000190056 SCV000243731 likely pathogenic not provided 2018-08-08 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in TSC2 is denoted c.1283_1285delCCT at the cDNA level and p.Ser428del (S428del) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ATCT[delCCT]ATAG. This deletion of a single Serine residue occurs at a position that is not conserved and is not located in a known functional domain. This variant was observed in at least two individuals with tuberous sclerosis complex (van Eeghen 2013, Au 2007). Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider TSC2 Ser428del to be a variant of uncertain significance.
Invitae RCV000475301 SCV000544460 likely pathogenic Tuberous sclerosis 2 2018-03-06 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 13 of the TSC2 mRNA (c.1283_1285delCCT). This leads to the deletion of 1 amino acid residue in the TSC2 protein (p.Ser428del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (rs137853983, ExAC no frequency). This variant has been reported in the literature in two individuals affected with, or suspected of having, tuberous sclerosis complex (PMID: 17304050, 22867869). ClinVar contains an entry for this variant (Variation ID: 49644). This variant has been reported in several individuals and four families affected with tuberous sclerosis complex in the Leiden Open-source Variation Database (PMID: 21520333). The available evidence is insufficient to conclude if this variant segregates with disease or not. However, in two of these individuals this variant has been reported to arise de novo. Prediction algorithms are not available for this variant. However, in the Leiden Open-source Variation Database, this variant has been reported to affect TSC2 protein function in vitro to a similar extent as a known TSC2 pathogenic variant (PMID: 21520333). This report has not been confirmed by published experimental studies. In summary, this variant is a rare in-frame deletion of 1 amino acid that is absent from general population and has been observed in affected individuals. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Tuberous sclerosis database (TSC2) RCV000042906 SCV000066702 not provided Tuberous sclerosis syndrome no assertion provided curation

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