Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000042431 | SCV000967731 | likely pathogenic | Tuberous sclerosis syndrome | 2018-04-06 | criteria provided, single submitter | clinical testing | The p.Tyr568His variant in TSC2 has been reported in at least 4 individuals with tuberous sclerosis complex (TSC), including at least one de novo occurrence (Ne llist 2008, LOVD-TSC2 database- http://chromium.lovd.nl/LOVD2/TSC). This variant was absent from large population studies. In vitro functional studies provide s ome evidence that the p.Tyr568His variant may impact protein function by impairi ng TSC1-TSC2 binding (Nellist 2008). Additionally, computational prediction tool s and conservation analysis suggest that the p.Tyr598His variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, the p.Tyr598His variant is likely pathogenic. ACMG/A MP Criteria applied (Richards 2015): PM2; PM6; PS3_Supporting; PP3; PS4_Moderate . |
| Labcorp Genetics |
RCV001852875 | SCV002282582 | likely pathogenic | Tuberous sclerosis 2 | 2021-04-23 | criteria provided, single submitter | clinical testing | 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. This sequence change replaces tyrosine with histidine at codon 598 of the TSC2 protein (p.Tyr598His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 18302728, 22974335, Invitae). ClinVar contains an entry for this variant (Variation ID: 49175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TSC2 protein function. This variant disrupts the p.Tyr598 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been observed in individuals with TSC2-related conditions (PMID:22903760, Invitae), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this variant affects TSC2 protein function (PMID: 18302728, 21309039). |
| Tuberous sclerosis database |
RCV000042431 | SCV000066222 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |