ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.2410T>C (p.Cys804Arg) (rs137853995)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189999 SCV000243671 pathogenic not provided 2014-05-07 criteria provided, single submitter clinical testing p.Cys804Arg (TGC>CGC): c.2410 T>C in exon 22 of the TSC2 gene (NM_000548.3)The C804R missense mutation in the TSC2 gene has been identified previously as a de novo mutation in a patient with tuberous sclerosis and is reported to destabilize the TSC1-TSC2 complex (TSC2 LOVD; Hoogeveen-Westerveld et al., 2011). It has also been identified as an apparently de novo mutation in other unrelated individuals at GeneDx. C804R was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, C804R is considered a disease-causing mutation. The variant is found in INFANT-EPI panel(s).
Athena Diagnostics Inc RCV000201105 SCV000255884 likely pathogenic Tuberous sclerosis 2 2015-09-18 criteria provided, single submitter clinical testing
Invitae RCV000201105 SCV000955348 likely pathogenic Tuberous sclerosis 2 2019-11-12 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 804 of the TSC2 protein (p.Cys804Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo individuals affected with TSC2-related disease (PMID: 21309039, 19747374). ClinVar contains an entry for this variant (Variation ID: 49725). Experimental studies have shown that this missense change destabilizes the TSC1-TSC2 complex (PMID: 21309039). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Tuberous sclerosis database (TSC2) RCV000042990 SCV000066788 not provided Tuberous sclerosis syndrome no assertion provided curation

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