Submissions for variant NM_000548.5(TSC2):c.281C>T (p.Pro94Leu)

gnomAD frequency: 0.00001  dbSNP: rs200045926

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471856	SCV000544442	likely benign	Tuberous sclerosis 2	2025-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV001797088	SCV002038796	uncertain significance	not provided	2021-06-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 18466115, 27535533, 28191889)
Ambry Genetics	RCV002436401	SCV002749505	likely benign	Hereditary cancer-predisposing syndrome	2023-03-17	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
All of Us Research Program, National Institutes of Health	RCV004000706	SCV004816937	uncertain significance	Tuberous sclerosis syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 94 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 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.
Fulgent Genetics, Fulgent Genetics	RCV005018756	SCV005644929	uncertain significance	Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2024-06-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004533162	SCV004709868	uncertain significance	TSC2-related disorder	2023-12-01	no assertion criteria provided	clinical testing	The TSC2 c.281C>T variant is predicted to result in the amino acid substitution p.Pro94Leu. This variant was identified in a large cohort study looking at neurodevelopmental disorder risk genes (Stessman et al. 2017. PubMed ID: 28191889). This variant has not been reported in a large population database, indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.