Submissions for variant NM_000548.5(TSC2):c.5092A>C (p.Ser1698Arg)

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV002286560	SCV002574924	uncertain significance	Tuberous sclerosis 2	2022-01-18	criteria provided, single submitter	clinical testing	description: A heterozygous missense variation in exon 40 of the TSC2 gene that results in the amino acid substitution of Arginine for Serine at codon 1698 (p.Ser1698Arg) was detected . The p.Ser1698Arg variant has not been reported in the 1000 genomes and gnomAD databases. The in silico predictions# of the variant are possibly damaging by PolyPhen-2 (HumDiv), and damaging by SIFT. The reference codon is conserved across species.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002286560	SCV003513736	uncertain significance	Tuberous sclerosis 2	2024-04-16	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with arginine, which is basic and polar, at codon 1698 of the TSC2 protein (p.Ser1698Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1707603). 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 with a negative predictive value of 95%. 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	RCV003308099	SCV003998655	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-22	criteria provided, single submitter	clinical testing	The p.S1698R variant (also known as c.5092A>C), located in coding exon 39 of the TSC2 gene, results from an A to C substitution at nucleotide position 5092. The serine at codon 1698 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV003322914	SCV004028355	uncertain significance	not provided	2023-02-20	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18466115)
Myriad Genetics, Inc.	RCV002286560	SCV005403763	benign	Tuberous sclerosis 2	2024-09-05	criteria provided, single submitter	clinical testing	This variant is considered benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.