Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000492813 | SCV000581956 | pathogenic | not provided | 2023-05-02 | criteria provided, single submitter | clinical testing | Reported previously as a heterozygous likely pathogenic variant in a patient with epilepsy; however, no further clinical or segregation information was provided (Truty et al., 2019); Published functional studies demonstrate a damaging effect showing that the variant disrupts the function of the TSC1-TSC2 complex (Wentink et al., 2012; Hoogeveen-Westerveld et al., 2013); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19028034, 21332470, 23389244, 11403047, 17120248, 28492532, 30255984, 31440721, 22903760, 27535533, 17304050) |
Invitae | RCV000013210 | SCV000644542 | pathogenic | Tuberous sclerosis 2 | 2023-03-07 | 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) 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. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects TSC2 function (PMID: 21332470, 22903760). ClinVar contains an entry for this variant (Variation ID: 12401). This missense change has been observed in individual(s) with mild manifestations of tuberous sclerosis complex (TSC) (PMID: 11403047). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 1503 of the TSC2 protein (p.Gln1503Pro). |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000043266 | SCV000697470 | pathogenic | Tuberous sclerosis syndrome | 2017-07-28 | criteria provided, single submitter | clinical testing | Variant summary: The TSC2 c.4508A>C (p.Gln1503Pro) variant involves the alteration of a conserved nucleotide that lies within the Rap GTPase activating protein domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120242 control chromosomes (ExAC and publication controls). The variant was identified in two families from the same geographical area with multiple affected individuals in each family. While the physical features typical of tuberous sclerosis were mild, affected individuals had significant neuropsychiatric symptoms including pervasive developmental disorder and autism. The variant cosegregated with disease completely in 14 affected and 9 unaffected individuals (Khare_JMG_2001). A functional study revealed the variant was unable to inhibit S6K phosphorylation in cultured cells (Wentink_Clin Genet_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. |
Ambry Genetics | RCV002316192 | SCV000851198 | pathogenic | Hereditary cancer-predisposing syndrome | 2016-08-12 | criteria provided, single submitter | clinical testing | The p.Q1503P pathogenic mutation (also known as c.4508A>C), located in coding exon 34 of the TSC2 gene, results from an A to C substitution at nucleotide position 4508. The glutamine at codon 1503 is replaced by proline, an amino acid with similar properties. This pathogenic mutation was identified in two unrelated four-generation families with tuberous sclerosis complex; it co-segregated with the disease in those families (Khare L et al. J. Med. Genet., 2001 May;38:347-9). Furthermore, in vitro assay of the Q1503P mutant protein revealed that this mutation significantly increases T389-phosphorylated S6 kinase, thereby preventing the TSC-TSC2-dependent inhibition of the target of rapamycin complex 1 (TORC1) activity (Wentink M et al. Clin. Genet., 2012 May;81:453-61; Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). Based on the available evidence, this variant is classified as a pathogenic mutation. |
Genome- |
RCV000013210 | SCV002040999 | likely pathogenic | Tuberous sclerosis 2 | 2021-11-07 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000013210 | SCV003806646 | likely pathogenic | Tuberous sclerosis 2 | 2023-01-31 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 11403047]. Functional studies indicate this variant impacts protein function [PMID: 21332470, 22903760]. This variant is expected to disrupt protein structure [internal Myriad data]. |
Baylor Genetics | RCV003460465 | SCV004205105 | pathogenic | Isolated focal cortical dysplasia type II | 2023-05-02 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000013210 | SCV000033457 | pathogenic | Tuberous sclerosis 2 | 2001-05-01 | no assertion criteria provided | literature only | |
Tuberous sclerosis database |
RCV000043266 | SCV000067068 | not provided | Tuberous sclerosis syndrome | no assertion provided | curation | ||
Gene |
RCV000013210 | SCV000245754 | not provided | Tuberous sclerosis 2 | no assertion provided | literature only |