Submissions for variant NM_000548.5(TSC2):c.4312C>T (p.Arg1438Trp)

dbSNP: rs778925833

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000190079	SCV000243754	uncertain significance	not provided	2014-10-15	criteria provided, single submitter	clinical testing	p.Arg1438Trp (CGG>TGG): c.4312 C>T in exon 34 of the TSC2 gene (NM_000548.3) A variant of unknown significance has been identified in the TSC2 gene. The R1438W variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. A different amino acid substitution at the same position (R1438Q) was reported as a de novo mutation in an individual with tuberous sclerosis (Roberts et al., 2004). R1438W was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R1438W variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, the R1438W variant alters a poorly conserved position in the protein. Additionally, it is not within any known functional domain of the tuberin protein, where many pathogenic missense mutations have been identified (Northrup et al., 2011; Au et al., 2007). Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in EPILEPSY panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000695662	SCV000824176	benign	Tuberous sclerosis 2	2023-12-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001022271	SCV001183986	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-09	criteria provided, single submitter	clinical testing	The p.R1438W variant (also known as c.4312C>T), located in coding exon 33 of the TSC2 gene, results from a C to T substitution at nucleotide position 4312. The arginine at codon 1438 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is poorly 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.
Genome-Nilou Lab	RCV000695662	SCV002040821	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462296	SCV004205117	uncertain significance	Isolated focal cortical dysplasia type II	2024-03-24	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003996900	SCV004834375	uncertain significance	Tuberous sclerosis syndrome	2024-01-11	criteria provided, single submitter	clinical testing