Submissions for variant NM_000368.5(TSC1):c.2829C>T (p.Ala943=) (rs4962081)

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000118693	SCV000169094	benign	not specified	2015-03-04	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,Partners HealthCare Personalized Medicine	RCV000118693	SCV000205282	benign	not specified	2013-02-21	criteria provided, single submitter	clinical testing	Ala943Ala in exon 22 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 9.1% (399/4406) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs4962081).
Ambry Genetics	RCV000162946	SCV000213433	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: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000118693	SCV000227885	benign	not specified	2014-07-31	criteria provided, single submitter	clinical testing
PreventionGenetics,PreventionGenetics	RCV000118693	SCV000303866	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000576543	SCV000478189	benign	Tuberous sclerosis 1	2018-01-13	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 Clinical Services Laboratory,Illumina	RCV000370584	SCV000478190	benign	Focal cortical dysplasia type II	2018-01-13	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 Inc	RCV000576543	SCV000677528	benign	Tuberous sclerosis 1	2017-04-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590200	SCV000696607	benign	not provided	2016-05-26	criteria provided, single submitter	clinical testing	Variant summary: The TSC1 c.2829C>T (p.Ala943Ala) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant along with 5/5 splice prediction tools predicting the variant not to have an impact on normal splicing. This variant was found in 9206/121392 control chromosomes (457 homozygotes), predominantly observed in the Latino, (143 homozygotes) subpopulation at a frequency of 0.1558127 (1804/11578). This frequency greatly exceeds the estimated maximal expected allele frequency of a pathogenic TSC1 variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of Latino origin. In addition, multiple clinical diagnostic laboratories classified this variant as Benign. Taken together, this variant is classified as Benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories	RCV001282237	SCV000884749	benign	none provided	2020-08-27	criteria provided, single submitter	clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute,Kanazawa Medical University	RCV000576543	SCV001430708	likely benign	Tuberous sclerosis 1	2020-07-10	criteria provided, single submitter	clinical testing
Invitae	RCV000576543	SCV001726098	benign	Tuberous sclerosis 1	2020-11-28	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC1)	RCV000042257	SCV000066044	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Tuberous sclerosis database (TSC1)	RCV000054906	SCV000083121	not provided	Urinary bladder cancer		no assertion provided	curation
Tuberous sclerosis database (TSC1)	RCV000055028	SCV000083246	not provided	Lymphangiomyomatosis; Tuberous sclerosis syndrome		no assertion provided	curation
Genetic Services Laboratory, University of Chicago	RCV000118693	SCV000153108	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.