ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.3284G>A (p.Ser1095Asn) (rs1555510754)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001042713 SCV001206413 pathogenic Tuberous sclerosis 2 2019-11-25 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1095 of the TSC2 protein (p.Ser1095Asn). The serine residue is weakly conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 28 of the TSC2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with tuberous sclerosis complex (Invitae, Leiden Open-source Variation Database (PMID: 21520333)). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 50058). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. For these reasons, this variant has been classified as Pathogenic.
Tuberous sclerosis database (TSC2) RCV000043324 SCV000067130 not provided Tuberous sclerosis syndrome no assertion provided curation

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