ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4952A>G (p.Asn1651Ser) (rs45517382)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000359328 SCV000329791 pathogenic not provided 2017-09-25 criteria provided, single submitter clinical testing The N1651S variant in the TSC2 gene has been reported multiple times previously in association with tuberous sclerosis complex (TSC) (Maheshwar et al., 1997; TSC2 LOVD). Functional studies suggest N1651S impairs the ability of tuberin to act as a GTPase activating protein (Tee et al., 2003). The N1651S variant is not observed in large population cohorts (Lek et al., 2016). The N1651S variant is a conservative amino acid substitution, and it occurs at a position that is conserved across species. Multiple missense variants in nearby residues have been reported in association with TSC (Stenson et al., 2014; TSC2 LOVD), supporting the functional importance of this region of the protein. Therefore, we interpret N1651S as a pathogenic variant.
Invitae RCV000543686 SCV000644583 pathogenic Tuberous sclerosis 2 2018-04-24 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1651 of the TSC2 protein (p.Asn1651Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with tuberous sclerosis (PMID: 12111193, 15024740, 9302281). ClinVar contains an entry for this variant (Variation ID: 49335). Experimental studies have shown that this variant affects the functional ability of the TSC2 protein to suppress mTOR signaling (PMID: 27078846, 14718525, 18550814, 18411301, 12906785). For these reasons, this variant has been classified as Pathogenic.
Tuberous sclerosis database (TSC2) RCV000042595 SCV000066389 not provided Tuberous sclerosis syndrome no assertion provided curation
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000042595 SCV000805048 likely pathogenic Tuberous sclerosis syndrome 2016-08-09 no assertion criteria provided clinical testing

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