Submissions for variant NM_000548.5(TSC2):c.3532C>G (p.Gln1178Glu)

gnomAD frequency: 0.00001  dbSNP: rs45517297

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000190020	SCV000243692	uncertain significance	not provided	2016-04-05	criteria provided, single submitter	clinical testing	This variant is denoted TSC2 c.3532C>G at the cDNA level, p.Gln1178Glu (Q1178E) at the protein level, and results in the change of a Glutamine to a Glutamic Acid (CAG>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. TSC2 Gln1178Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamine and Glutamic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. TSC2 Gln1178Glu occurs at a position that is not conserved and is not located in a known functional domain (Gumbinger 2009). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether TSC2 Gln1178Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000551233	SCV000644449	uncertain significance	Tuberous sclerosis 2	2023-12-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1178 of the TSC2 protein (p.Gln1178Glu). 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: 207746). 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	RCV001020544	SCV001182037	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-08	criteria provided, single submitter	clinical testing	The p.Q1178E variant (also known as c.3532C>G), located in coding exon 29 of the TSC2 gene, results from a C to G substitution at nucleotide position 3532. The glutamine at codon 1178 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000551233	SCV002040782	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing