Submissions for variant NM_000548.5(TSC2):c.3454A>G (p.Ser1152Gly)

dbSNP: rs772215032

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001768600	SCV001992393	uncertain significance	not provided	2019-04-25	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
Labcorp Genetics (formerly Invitae), Labcorp	RCV002032826	SCV002230971	uncertain significance	Tuberous sclerosis 2	2024-07-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1152 of the TSC2 protein (p.Ser1152Gly). 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: 1305393). 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	RCV003163832	SCV003911466	likely benign	Hereditary cancer-predisposing syndrome	2022-11-30	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV004008997	SCV004822290	uncertain significance	Tuberous sclerosis syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 1152 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.