Submissions for variant NM_000548.5(TSC2):c.4584G>T (p.Glu1528Asp)

dbSNP: rs199848388

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000815033	SCV000955474	uncertain significance	Tuberous sclerosis 2	2024-01-03	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1528 of the TSC2 protein (p.Glu1528Asp). 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: 41743). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV001022737	SCV001184507	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-20	criteria provided, single submitter	clinical testing	The p.E1528D variant (also known as c.4584G>T), located in coding exon 35 of the TSC2 gene, results from a G to T substitution at nucleotide position 4584. The glutamic acid at codon 1528 is replaced by aspartic acid, an amino acid with highly similar properties. This variant was detected as a secondary finding in 1 out of 572 ClinSeq participants, unselected for personal or family history of cancer, who underwent exome sequencing; however, the clinical information for this particular individual was not provided (Johnston JJ et al. Am. J. Hum. Genet., 2012 Jul;91:97-108). This amino acid position is well conserved in available vertebrate species. In addition, as a missense variant, this alteration is predicted to be tolerated by in silico analysis. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data).. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000815033	SCV002040839	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003460546	SCV004206883	uncertain significance	Isolated focal cortical dysplasia type II	2023-07-11	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034660	SCV000043543	variant of unknown significance	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Uncertain significance.