Submissions for variant NM_000548.5(TSC2):c.1317C>A (p.Asp439Glu)

dbSNP: rs777457815

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000539682	SCV000644228	benign	Tuberous sclerosis 2	2025-01-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000562035	SCV000675678	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-19	criteria provided, single submitter	clinical testing	The p.D439E variant (also known as c.1317C>A), located in coding exon 12 of the TSC2 gene, results from a C to A substitution at nucleotide position 1317. The aspartic acid at codon 439 is replaced by glutamic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, glutamic acid is the reference amino acid in other vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Genome-Nilou Lab	RCV000539682	SCV002040602	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
GeneDx	RCV003236813	SCV003935680	uncertain significance	not provided	2023-06-20	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics	RCV003459238	SCV004206876	uncertain significance	Isolated focal cortical dysplasia type II	2023-07-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003999248	SCV004815218	uncertain significance	Tuberous sclerosis syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 439 of the TSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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 not been identified 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.