Submissions for variant NM_000548.5(TSC2):c.2656G>C (p.Val886Leu)

dbSNP: rs999523698

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487076	SCV000572422	uncertain significance	not provided	2016-12-05	criteria provided, single submitter	clinical testing	This variant is denoted TSC2 c.2656G>C at the cDNA level, p.Val886Leu (V886L) at the protein level, and results in the change of a Valine to a Leucine (GTG>CTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. TSC2 Val886Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. TSC2 Val886Leu occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether TSC2 Val886Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV001037910	SCV001201346	uncertain significance	Tuberous sclerosis 2	2023-09-25	criteria provided, single submitter	clinical testing	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. ClinVar contains an entry for this variant (Variation ID: 422850). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 886 of the TSC2 protein (p.Val886Leu). 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.
Genome-Nilou Lab	RCV001037910	SCV002040714	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002455934	SCV002739868	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-17	criteria provided, single submitter	clinical testing	The p.V886L variant (also known as c.2656G>C), located in coding exon 23 of the TSC2 gene, results from a G to C substitution at nucleotide position 2656. The valine at codon 886 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly 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.