Submissions for variant NM_000548.5(TSC2):c.3599G>A (p.Arg1200Gln)

dbSNP: rs397515225

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000421784	SCV000530976	uncertain significance	not provided	2023-01-10	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual reported to have tuberous sclerosis complex (Ding et al., 2021); This variant is associated with the following publications: (PMID: 34252879)
Invitae	RCV000706223	SCV000835262	uncertain significance	Tuberous sclerosis 2	2023-10-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1200 of the TSC2 protein (p.Arg1200Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in at least one individual who was not affected with TSC2-related conditions (Invitae). ClinVar contains an entry for this variant (Variation ID: 388628). 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. This variant disrupts the p.Arg1200 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8824881, 9463313, 18792920, 21332470, 22867869, 25039834, 28149746, 29308833; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Genome-Nilou Lab	RCV000706223	SCV002039771	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002258893	SCV002533426	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-04	criteria provided, single submitter	curation
Ambry Genetics	RCV002258893	SCV002615348	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-14	criteria provided, single submitter	clinical testing	The p.R1200Q variant (also known as c.3599G>A), located in coding exon 29 of the TSC2 gene, results from a G to A substitution at nucleotide position 3599. The arginine at codon 1200 is replaced by glutamine, an amino acid with highly similar properties. 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.
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV000706223	SCV003807816	uncertain significance	Tuberous sclerosis 2	2022-09-02	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 supporting, PM5 moderated, PP3 supporting