ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4420A>G (p.Arg1474Gly)

gnomAD frequency: 0.00001  dbSNP: rs766719443
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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 RCV000462201 SCV000544438 likely benign Tuberous sclerosis 2 2024-11-14 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004000704 SCV004829233 uncertain significance Tuberous sclerosis syndrome 2023-09-17 criteria provided, single submitter clinical testing This missense variant replaces arginine with glycine at codon 1474 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 TSC2-related disorders in the literature. This variant has been identified in 2/238010 chromosomes 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 RCV004678710 SCV005174551 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-26 criteria provided, single submitter clinical testing The p.R1474G variant (also known as c.4420A>G), located in coding exon 33 of the TSC2 gene, results from an A to G substitution at nucleotide position 4420. The arginine at codon 1474 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been reported in an individual from a cohort of 1191 cancer index patients who underwent clinical evaluation and testing with multigene panels (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This amino acid position is well conserved in available vertebrate species. 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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