ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.3484C>T (p.Pro1162Ser)

gnomAD frequency: 0.00001  dbSNP: rs895935495
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000470235 SCV000544485 uncertain significance Tuberous sclerosis 2 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1162 of the TSC2 protein (p.Pro1162Ser). 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: 406071). 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.
Ambry Genetics RCV001020411 SCV001181887 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-29 criteria provided, single submitter clinical testing The p.P1162S variant (also known as c.3484C>T), located in coding exon 29 of the TSC2 gene, results from a C to T substitution at nucleotide position 3484. In one study, this alteration was identified in one individual from a cohort of patients with clinically suspected TSC; the study did not specify the patient's clinical features (Meng Y et al. J Hum Genet, 2021 Mar;66:227-236). The proline at codon 1162 is replaced by serine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001560998 SCV001783516 uncertain significance not provided 2019-05-23 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This substitution does not occur within known functional domains of the tuberin protein, where many pathogenic missense variants have been identified (Northrup et al., 2018; Au et al., 2007)
Genome-Nilou Lab RCV000470235 SCV002040777 uncertain significance Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing

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