Submissions for variant NM_000368.5(TSC1):c.1760A>G (p.Lys587Arg)

gnomAD frequency: 0.01347  dbSNP: rs118203576

Total submissions: 27

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000118691	SCV000153106	benign	not specified	2013-08-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000118691	SCV000169087	benign	not specified	2012-04-26	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.
Ambry Genetics	RCV000163265	SCV000213793	benign	Hereditary cancer-predisposing syndrome	2014-11-25	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)	RCV000118691	SCV000226221	benign	not specified	2014-07-16	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000005405	SCV000257670	benign	Tuberous sclerosis 1	2015-02-05	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000163265	SCV000267094	benign	Hereditary cancer-predisposing syndrome	2015-10-07	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224245	SCV000281085	benign	not provided	2016-01-21	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000118691	SCV000303852	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000005405	SCV000478225	benign	Tuberous sclerosis 1	2018-03-06	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	RCV000303027	SCV000478226	benign	Isolated focal cortical dysplasia type II	2018-03-06	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000118691	SCV000540595	benign	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Disclaimer: This variant has not undergone full assessment. The following are pr eliminary notes: Frequency
Labcorp Genetics (formerly Invitae), Labcorp	RCV000005405	SCV000562464	benign	Tuberous sclerosis 1	2024-02-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000005405	SCV000677527	benign	Tuberous sclerosis 1	2017-05-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000118691	SCV000696601	benign	not specified	2021-11-02	criteria provided, single submitter	clinical testing	Variant summary: TSC1 c.1760A>G (p.Lys587Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.026 in 252466 control chromosomes, predominantly at a frequency of 0.17 within the Latino subpopulation in the gnomAD database, including 614 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 6,800-fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC1 causing Tuberous Sclerosis Complex phenotype (2.5e-05), strongly suggesting that the variant is a benign polymorphism. c.1760A>G has been reported in the literature in Tuberous Sclerosis Complex patients with other known causal variants (e.g. TSC2 c.648+1G>A; van Slegtenhorst_1997), providing supporting evidence for a benign role. Nine ClinVar submitters (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000005405	SCV000782388	benign	Tuberous sclerosis 1	2016-11-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224245	SCV000884745	benign	not provided	2023-11-11	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000005405	SCV002040420	benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000118691	SCV002774051	benign	not specified	2021-06-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000005405	SCV004360822	benign	Tuberous sclerosis 1	2022-09-20	criteria provided, single submitter	clinical testing
Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	RCV000118691	SCV005087943	benign	not specified	2024-07-15	criteria provided, single submitter	clinical testing	This variant is classified as Benign based on local population frequency. This variant was detected in 27% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 25. Only high quality variants are reported.
Breakthrough Genomics, Breakthrough Genomics	RCV000224245	SCV005321585	benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000005405	SCV000025587	uncertain significance	Tuberous sclerosis 1	1998-07-01	no assertion criteria provided	literature only
Tuberous sclerosis database (TSC1)	RCV000042078	SCV000065862	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
ITMI	RCV000118691	SCV000086407	not provided	not specified	2013-09-19	no assertion provided	reference population
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000118691	SCV001809191	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000224245	SCV001917792	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000118691	SCV001975501	benign	not specified		no assertion criteria provided	clinical testing