ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1958G>A (p.Arg653Lys)

dbSNP: rs876658202
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220242 SCV000273139 uncertain significance Hereditary cancer-predisposing syndrome 2014-12-16 criteria provided, single submitter clinical testing The p.R653K variant (also known as c.1958G>A), located in coding exon 18 of the TSC2 gene, results from a G to A substitution at nucleotide position 1958. The arginine at codon 653 is replaced by lysine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6483 samples (12966 alleles) with coverage at this position. This amino acid position is not well conserved in available vertebrate species. To date, this alteration has been detected with an allele frequency of approximately 0.06% (greater than 1800 alleles tested) in our clinical cohort. In addition, this alteration is predicted to be probably damaging by PolyPhen but tolerated by SIFT in silico analyses. Since supporting evidence is limited at this time, the clinical significance of p.R653K remains unclear.
Invitae RCV001853503 SCV002229048 uncertain significance Tuberous sclerosis 2 2023-05-01 criteria provided, single submitter clinical testing 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. 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. ClinVar contains an entry for this variant (Variation ID: 229799). This variant has not been reported in the literature in individuals affected with TSC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 653 of the TSC2 protein (p.Arg653Lys).

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