Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000472366 | SCV000544328 | uncertain significance | Tuberous sclerosis 2 | 2023-02-14 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 57 of the TSC2 protein (p.Arg57His). This variant is present in population databases (rs397514949, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of TSC2-related conditions (PMID: 21520333). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 64932). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21309039). 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. |
| Ambry Genetics | RCV002399416 | SCV002712265 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-01-23 | criteria provided, single submitter | clinical testing | The p.R57H variant (also known as c.170G>A), located in coding exon 2 of the TSC2 gene, results from a G to A substitution at nucleotide position 170. The arginine at codon 57 is replaced by histidine, an amino acid with highly similar properties. Functional analysis of this alteration a TSC1 binding signal similar to wildtype; a slightly decreased TSC2 signal, suggesting instability; and a significantly increased phospho-S6K signal (Hoogeveen-Westerveld M et al. Hum. Mutat., 2011 Apr;32:424-35). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Athena Diagnostics Inc | RCV003482235 | SCV004229359 | uncertain significance | not provided | 2023-01-24 | criteria provided, single submitter | clinical testing | Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is uninformative in assessment of its pathogenicity (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. (PMID: 21309039) The variant is located in a region that is considered important for protein function and/or structure. Computational tools predict that this variant is damaging. |
| Tuberous sclerosis database |
RCV000055135 | SCV000083353 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation |