Submissions for variant NM_000548.5(TSC2):c.1882C>T (p.Arg628Cys)

gnomAD frequency: 0.00003  dbSNP: rs45437797

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460911	SCV000544578	likely benign	Tuberous sclerosis 2	2024-01-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV002256251	SCV002531013	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	curation
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000460911	SCV002559802	likely pathogenic	Tuberous sclerosis 2	2022-07-19	criteria provided, single submitter	clinical testing	According to ACMG GL 2015, this variant located in Hamartin binding domain (PM1), Arg628Gly has been determined to be pathogenic (PM5), assumed de novo (PM6), multiple lines of computational evidence support a deleterious effect (PP3), and detected in the patient with clinically definitive tuberous sclerosis complex (PP4).
Ambry Genetics	RCV002256251	SCV002717730	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-30	criteria provided, single submitter	clinical testing	The p.R628C variant (also known as c.1882C>T), located in coding exon 17 of the TSC2 gene, results from a C to T substitution at nucleotide position 1882. The arginine at codon 628 is replaced by cysteine, an amino acid with highly dissimilar properties. In one study, this variant was identified in 1 of 283 patients with a definite or suspected clinical diagnosis of tuberous sclerosis complex (TSC) (Togi S et al. Int J Mol Sci. 2022 Sep;23(19). However, this variant has also been detected in multiple individuals with no reported features of TSC2-associated disease (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
All of Us Research Program, National Institutes of Health	RCV004000726	SCV004814941	uncertain significance	Tuberous sclerosis syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 628 of the TSC2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with tuberous sclerosis complex in the literature. This variant has been identified in 8/250502 chromosomes 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.
GeneDx	RCV004719823	SCV005326080	uncertain significance	not provided	2024-01-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 36232477)