Submissions for variant NM_000548.5(TSC2):c.2071C>G (p.Arg691Gly)

dbSNP: rs760489473

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000532403	SCV000644316	uncertain significance	Tuberous sclerosis 2	2025-01-02	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 691 of the TSC2 protein (p.Arg691Gly). This variant is not present in population databases (gnomAD no frequency). 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: 467920). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
GeneDx	RCV001770440	SCV001994035	uncertain significance	not provided	2019-07-01	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Genome-Nilou Lab	RCV000532403	SCV002040676	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999264	SCV004817463	uncertain significance	Tuberous sclerosis syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 691 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV004024043	SCV005036247	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-23	criteria provided, single submitter	clinical testing	The p.R691G variant (also known as c.2071C>G), located in coding exon 18 of the TSC2 gene, results from a C to G substitution at nucleotide position 2071. The arginine at codon 691 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV004568829	SCV005054478	uncertain significance	Isolated focal cortical dysplasia type II	2024-01-09	criteria provided, single submitter	clinical testing