Submissions for variant NM_000368.5(TSC1):c.947G>A (p.Arg316Gln)

gnomAD frequency: 0.00002  dbSNP: rs375956049

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000366220	SCV000341334	uncertain significance	not provided	2016-05-12	criteria provided, single submitter	clinical testing
Invitae	RCV001085318	SCV000552269	likely benign	Tuberous sclerosis 1	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000366220	SCV001797178	likely benign	not provided	2019-12-13	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000366220	SCV002009232	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001085318	SCV002040132	likely benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002446526	SCV002683125	likely benign	Hereditary cancer-predisposing syndrome	2022-01-07	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.
Clinical Genomics Laboratory, Washington University in St. Louis	RCV001085318	SCV004177035	uncertain significance	Tuberous sclerosis 1	2023-09-15	criteria provided, single submitter	clinical testing	The TSC1 c.947G>A (p.Arg316Gln) variant was identified at a near-heterozygous allelic fraction. This variant, to our knowledge, has not been reported in the medical literature. This variant has been reported in the ClinVar database as a variant of uncertain significance by two submitters and a likely benign variant by multiple submitters (ClinVar ID: 287541). This variant is absent from the general population (gnomAD v.3.1.2), indicating it is not a common variant. Computational predictors are uncertain as to the impact of this variant on the TSC1 function. Due to limited information and based on ACMG/AMP guidelines for variant interpretation (Richards S et al., PMID: 25741868), the clinical significance of this variant is uncertain at this time.
All of Us Research Program, National Institutes of Health	RCV003995780	SCV004840506	uncertain significance	Tuberous sclerosis syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 316 of the TSC1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 TSC1-related disorders in the literature. This variant has been identified in 4/251272 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.