Submissions for variant NM_000548.5(TSC2):c.2054C>G (p.Pro685Arg)

dbSNP: rs959165669

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000423620	SCV000523093	uncertain significance	not provided	2022-09-15	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; Observed in a patient with autism spectrum disorder (Saskin et al., 2017); This variant is associated with the following publications: (PMID: 30842500, 28250423)
Invitae	RCV000558616	SCV000644315	uncertain significance	Tuberous sclerosis 2	2023-08-16	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. ClinVar contains an entry for this variant (Variation ID: 382914). This missense change has been observed in individual(s) with autism (PMID: 28250423). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 685 of the TSC2 protein (p.Pro685Arg). 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.
Genome-Nilou Lab	RCV000558616	SCV002040674	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003298436	SCV003988606	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing	The p.P685R variant (also known as c.2054C>G), located in coding exon 18 of the TSC2 gene, results from a C to G substitution at nucleotide position 2054. The proline at codon 685 is replaced by arginine, an amino acid with dissimilar 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.