Variants
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rs966695764

  • Uncertain significance
  • Likely benign

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Description

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.

This sequence change replaces glutamic acid with aspartic acid at codon 1789 of the TSC2 protein (p.Glu1789Asp). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (ExAC 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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.

Reference Allele

G


Alternative Allele

A

C

Chromosome

16


Location

2088553


Variant Type

SNP

Genes

ClinVar

Name

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


Allele

C


Clinical Significance

Uncertain significance

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