Submissions for variant NM_000368.5(TSC1):c.1335A>G (p.Glu445=)

gnomAD frequency: 0.15974  dbSNP: rs7862221

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000118690	SCV000169083	benign	not specified	2013-10-07	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000118690	SCV000200858	benign	not specified	2013-02-21	criteria provided, single submitter	clinical testing	Glu445Glu in exon 14 of TSC1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 21.9% (965/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs7862221).
Ambry Genetics	RCV000162953	SCV000213440	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Eurofins Ntd Llc (ga)	RCV000118690	SCV000226017	benign	not specified	2014-07-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000118690	SCV000303846	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000287833	SCV000478237	benign	Isolated focal cortical dysplasia type II	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV000576803	SCV000478238	benign	Tuberous sclerosis 1	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Athena Diagnostics	RCV000576803	SCV000677526	benign	Tuberous sclerosis 1	2017-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586425	SCV000696599	benign	not provided	2016-05-26	criteria provided, single submitter	clinical testing	Variant summary: The TSC1 c.1335A>G (p.Glu445Glu) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change 2 nucleotides from the exon14-intron13 boundary. One in silico tool predicts a polymorphism outcome for this variant. 5/5 Alamut algorithms predict no significant change to the cononical splice acceptor site, while 2/5 predict a strengthening of a cryptic splice acceptor site. This variant was found in 16480/120190 control chromosomes (1225 homozygotes) at a frequency of 0.1371162, which is approximately 5485 times the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories classified this variant as benign, and it has been reported in the literature as a normal population variant (PMID: 18538015). Taken together and based on the high allele frequency in the general population, this variant is classified as Benign.
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000576803	SCV001430713	benign	Tuberous sclerosis 1	2020-07-10	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586425	SCV001472438	benign	not provided	2023-11-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000576803	SCV001722509	benign	Tuberous sclerosis 1	2024-02-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000576803	SCV002040444	benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000576803	SCV004015644	benign	Tuberous sclerosis 1	2023-07-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000576803	SCV004360827	benign	Tuberous sclerosis 1	2019-03-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000042015	SCV004840465	benign	Tuberous sclerosis syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000586425	SCV005321588	benign	not provided		criteria provided, single submitter	not provided
Tuberous sclerosis database (TSC1)	RCV000042015	SCV000065797	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Genetic Services Laboratory, University of Chicago	RCV000118690	SCV000153105	likely benign	not specified		no assertion criteria provided	clinical testing	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed.
Clinical Genetics, Academic Medical Center	RCV000118690	SCV001920314	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000118690	SCV001973783	benign	not specified		no assertion criteria provided	clinical testing