ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.848+281C>T (rs45517132)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000457139 SCV000544426 pathogenic Tuberous sclerosis 2 2019-12-16 criteria provided, single submitter clinical testing This sequence change falls in intron 9 of the TSC2 gene. It does not directly change the encoded amino acid sequence of the TSC2 protein. This variant is not present in population databases (rs45517132, 1KG no frequency). This variant has been reported in the literature in individuals meeting clinical diagnostic criteria for tuberous sclerosis complex (TSC), where it was identified as a de novo or germline mosaic variant in one of the individuals (PMID: 10533066, 26540169). It is also known as IVS8+281C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 49923). Experimental studies using patient-derived RNA have shown that this variant affects mRNA splicing, leading to the activation of cryptic splice sites in intron 9 (also described as intron 8 in the literature), which creates a cryptic exon resulting in a frameshift and premature truncation (PMID: 11068191, 10533066). RNA secondary structure analysis indicated that this variant induces structural functionality of an intron with branchpoint and splice sites, incorporating a cryptic exon into the mature transcripts (PMID: 11068191). For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197516 SCV001368292 pathogenic CNS disorder 2018-12-21 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PS4,PP3,PP4. This variant was detected in heterozygous state.
Centogene AG - the Rare Disease Company RCV000457139 SCV001426479 pathogenic Tuberous sclerosis 2 criteria provided, single submitter clinical testing
Tuberous sclerosis database (TSC2) RCV000043190 SCV000066991 not provided Tuberous sclerosis syndrome no assertion provided curation

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