ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4958C>T (p.Ser1653Phe)

dbSNP: rs45517383
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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 RCV001242240 SCV001415311 uncertain significance Tuberous sclerosis 2 2024-10-25 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1653 of the TSC2 protein (p.Ser1653Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis (PMID: 14756965, 15024740). ClinVar contains an entry for this variant (Variation ID: 49336). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 22903760). 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.
Neuberg Centre For Genomic Medicine, NCGM RCV001242240 SCV005400934 uncertain significance Tuberous sclerosis 2 2023-06-22 criteria provided, single submitter clinical testing The observed missense variant c.4958C>T(p.Ser1653Phe) in TSC2 gene has been reported previously in an individual with Tuberous sclerosis complex (Feng JH, et al., 2004). A different amino acid change 4957T>C (p.Ser1653Pro) as a known pathogenic variant has been reported in ClinVar. The (p.Ser1653Phe) variant is absent in gnomAD Exomes. It has been submitted to ClinVar as Uncertain Significance. The amino acid Ser at position 1653 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The reference amino acid p.Ser1653Phe in TSC2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Since, study on multiple affected individuals and functional impact of the variant is not available. For these reasons, this variant has been classified as Uncertain Significance.
Tuberous sclerosis database (TSC2) RCV000042596 SCV000066390 not provided Tuberous sclerosis syndrome no assertion provided curation

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