ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2666C>T (p.Ala889Val) (rs137854155)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201152 SCV000255887 pathogenic Tuberous sclerosis 2 2012-07-05 criteria provided, single submitter clinical testing
Invitae RCV000201152 SCV000765936 uncertain significance Tuberous sclerosis 2 2017-10-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 889 of the TSC2 protein (p.Ala889Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family with 2 members affected with Tuberous Sclerosis Complex in the Leiden Open-source Variation Database (PMID: 21309039, 21520333). ClinVar contains an entry for this variant (Variation ID: 49586). Experimental studies have shown that this missense change disrupts the protein stability and causes a higher T389/S6K ratio than the wild type TSC2, indicating inability of this variant to inhibit mTOR activity (PMID: 21309039). A different missense substitution at this codon (p.Ala889Pro) has been reported to be de novo and determined to be pathogenic (PMID: 22903760, 21520333). This suggests that the alanine residue is critical for TSC2 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Tuberous sclerosis database (TSC2) RCV000042847 SCV000066643 not provided Tuberous sclerosis syndrome no assertion provided curation

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