Submissions for variant NM_000548.5(TSC2):c.910T>C (p.Trp304Arg)

dbSNP: rs397515108

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000795349	SCV000934805	likely pathogenic	Tuberous sclerosis 2	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces tryptophan, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 304 of the TSC2 protein (p.Trp304Arg). This variant is present in population databases (rs397515108, gnomAD 0.003%). This missense change has been observed in individuals with clinical features of tuberous sclerosis complex (PMID: 21520333, 31291687; Invitae). ClinVar contains an entry for this variant (Variation ID: 65143). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TSC2 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV001562466	SCV001785233	likely pathogenic	not provided	2023-03-07	criteria provided, single submitter	clinical testing	Previously reported in a newborn with cardiac rhabdomyomas; the mother had a history of epilepsy and renal hypoplasia, however it was unclear if she also harbored the variant (Mariscal-Mendizabal et al., 2019); Unpublished functional studies demonstrate reduced activity of TSC complex and a significant increase in the T389/S6K ratio compared to WT TSC2 (TSC2-LOVD); In silico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: 30986793, 31291687, 18466115, 23514105)
Genome-Nilou Lab	RCV000795349	SCV002041113	uncertain significance	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002054888	SCV002496013	uncertain significance	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-03-30	criteria provided, single submitter	clinical testing	TSC2 NM_000548.4 exon 10 p.Trp304Arg (c.910T>C): This variant has been reported in the literature in one individual with a cardiac rhabdomyoma and has been reported in the LOVD TSC2 datavase (Mariscal-Mendizábal 2019 PMID:31291687, https://databases.lovd.nl/shared/variants/TSC2). This variant is not present in large control databases but is present in ClinVar (Variation ID:65143). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Ambry Genetics	RCV002371896	SCV002685967	uncertain significance	Hereditary cancer-predisposing syndrome	2019-10-10	criteria provided, single submitter	clinical testing	The p.W304R variant (also known as c.910T>C), located in coding exon 9 of the TSC2 gene, results from a T to C substitution at nucleotide position 910. The tryptophan at codon 304 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.
PreventionGenetics, part of Exact Sciences	RCV003407436	SCV004109101	likely pathogenic	TSC2-related condition	2023-01-20	criteria provided, single submitter	clinical testing	The TSC2 c.910T>C variant is predicted to result in the amino acid substitution p.Trp304Arg. This variant has been reported prenatally in a fetus with cardiac rhabdomyoma and supraventricular tachycardia (Table 1, Mariscal-Mendizábal et al. 2019. PubMed ID: 31291687). The mother had a personal history of epilepsy and renal hypoplasia but was not tested for the variant. This variant is reported in the Lieden Open Variation Database (LOVD) database, which cites unpublished in vitro experimental data suggesting this variant impacts protein function (Database ID: TSC2_001152; http://chromium.lovd.nl/LOVD2/TSC/; Fokkema et al. 2011. PubMed ID: 21520333). This variant has also been reported in a renal cell carcinoma specimen from an individual with suspected tuberous sclerosis complex (TSC; Table 2, Parilla et al. 2019. PubMed ID: 30986793). At PreventionGenetics, this variant has been observed to co segregate with TSC in a mother and three offspring (Internal Data, PreventionGenetics). Of note, the variant was absent in a fourth unaffected offspring. This variant is reported in 1 of ~223,000 alleles in gnomAD (https://gnomad.broadinstitute.org/variant/16-2108809-T-C). It has conflicting interpretations of likely pathogenic and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/65143/). This variant is interpreted as likely pathogenic.
Tuberous sclerosis database (TSC2)	RCV000055358	SCV000083578	not provided	Tuberous sclerosis syndrome		no assertion provided	curation