ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5367G>C (p.Glu1789Asp)

dbSNP: rs966695764
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000688858 SCV000816484 uncertain significance Tuberous sclerosis 2 2023-12-10 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 1789 of the TSC2 protein (p.Glu1789Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of TSC2-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 568482). 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 RCV001023979 SCV001185928 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-13 criteria provided, single submitter clinical testing The p.E1789D variant (also known as c.5367G>C), located in coding exon 41 of the TSC2 gene, results from a G to C substitution at nucleotide position 5367. The glutamic acid at codon 1789 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is not well 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 RCV000688858 SCV002040898 uncertain significance Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002499223 SCV002776418 uncertain significance Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2 2021-10-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355129 SCV001549918 uncertain significance not provided no assertion criteria provided clinical testing The TSC2 p.Glu1545Asp variant was not identified in the literature, nor was it found in the following population databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The variant was identified in dbSNP (ID: rs966695764) and in ClinVar where it was classified by Invitae as a variant of uncertain significance for Tuberous sclerosis 2. The variant was reported in LOVD 3.0 as likely benign but was not identified in Cosmic or MutDB. Four of four in silico programs (SpliceSiteFinder-Like, MaxEntScan, NNSPLICE, and GeneSplicer) predict a greater than 10% change in splicing and loss of a non-canonical 5' splice site. Since this 5' splice site is not a canonical splice site it is unlikely that the predicted loss has any effect. The variant is located at a residue that is conserved in mammals but not in other species. Four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, and BLOSUM) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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