ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.3893T>C (p.Val1298Ala)

gnomAD frequency: 0.00001  dbSNP: rs758677443
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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 RCV000700001 SCV000828736 uncertain significance Tuberous sclerosis 2 2023-05-03 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 1298 of the TSC2 protein (p.Val1298Ala). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 577294). 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. 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 RCV002360791 SCV002623607 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-28 criteria provided, single submitter clinical testing The p.V1298A variant (also known as c.3893T>C), located in coding exon 32 of the TSC2 gene, results from a T to C substitution at nucleotide position 3893. The valine at codon 1298 is replaced by alanine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV003999700 SCV004836319 uncertain significance Tuberous sclerosis syndrome 2023-12-18 criteria provided, single submitter clinical testing This missense variant replaces valine with alanine at codon 1298 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 tuberous sclerosis complex 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.

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