Submissions for variant NM_000548.5(TSC2):c.3212C>T (p.Thr1071Ile)

dbSNP: rs45498892

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000465303	SCV000544490	uncertain significance	Tuberous sclerosis 2	2023-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 1071 of the TSC2 protein (p.Thr1071Ile). 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: 406076). 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) has been performed at Invitae 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. This variant disrupts the p.Thr1071 amino acid residue in TSC2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1112665). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513743	SCV000610258	uncertain significance	not provided	2017-08-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000574600	SCV000664679	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-25	criteria provided, single submitter	clinical testing	The p.T1071I variant (also known as c.3212C>T), located in coding exon 27 of the TSC2 gene, results from a C to T substitution at nucleotide position 3212. The threonine at codon 1071 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab	RCV000465303	SCV002040751	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000513743	SCV002762332	uncertain significance	not provided	2022-12-02	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge