ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4706A>G (p.Tyr1569Cys)

dbSNP: rs2090771064
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001229107 SCV001401543 uncertain significance Tuberous sclerosis 2 2024-05-21 criteria provided, single submitter clinical testing This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 1569 of the TSC2 protein (p.Tyr1569Cys). 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: 956326). 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.
All of Us Research Program, National Institutes of Health RCV004004828 SCV004837024 uncertain significance Tuberous sclerosis syndrome 2023-10-06 criteria provided, single submitter clinical testing This missense variant replaces tyrosine with cysteine at codon 1569 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TSC2-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV004951369 SCV005526084 uncertain significance Hereditary cancer-predisposing syndrome 2024-06-29 criteria provided, single submitter clinical testing The p.Y1569C variant (also known as c.4706A>G), located in coding exon 36 of the TSC2 gene, results from an A to G substitution at nucleotide position 4706. The tyrosine at codon 1569 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

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