Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000189987 | SCV000243658 | uncertain significance | not provided | 2013-10-08 | criteria provided, single submitter | clinical testing | p.Met589Lys (ATG>AAG): c.1766 T>A in exon 17 of the TSC2 gene (NM_000548.3)The Met589Lys variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It 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. This variant is a non-conservative amino acid substitution of an uncharged, non-polar Methionine residue to a positively charged, polar Lysine residue. However, Met598Lys alters a position that is not conserved across species in the tuberin protein and the amino acid substitution does not occur within known functional domains of the tuberin protein, where many pathogenic missense mutations have been identified (Northrup et al., 2011; Au et al., 2007). In addition, in silico analysis is inconsistent with regard to the effect this variant may have on the protein structure/function. Therefore, based on the currently available information, it is unclear whether Met589Lys is a disease-causing mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). |
Invitae | RCV003626610 | SCV004526797 | uncertain significance | Tuberous sclerosis 2 | 2023-05-22 | criteria provided, single submitter | clinical testing | 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 not expected to disrupt TSC2 protein function. ClinVar contains an entry for this variant (Variation ID: 207721). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 589 of the TSC2 protein (p.Met589Lys). 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. |