Submissions for variant NM_000368.5(TSC1):c.250G>A (p.Ala84Thr)

gnomAD frequency: 0.00036  dbSNP: rs118203357

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000163475	SCV000214030	likely benign	Hereditary cancer-predisposing syndrome	2018-10-05	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.
Eurofins Ntd Llc (ga)	RCV000122183	SCV000230916	benign	not specified	2015-03-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234434	SCV000284703	benign	Tuberous sclerosis 1	2025-02-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000122183	SCV000303862	likely benign	not specified		criteria provided, single submitter	clinical testing
GeneDx	RCV000122183	SCV000514986	benign	not specified	2015-04-03	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.
Illumina Laboratory Services, Illumina	RCV001167327	SCV001329808	benign	Isolated 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.
Illumina Laboratory Services, Illumina	RCV000234434	SCV001329809	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122183	SCV001478624	benign	not specified	2021-01-30	criteria provided, single submitter	clinical testing	Variant summary: TSC1 c.250G>A (p.Ala84Thr) results in a non-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 0.00072 in 250968 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 29 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 benign. To our knowledge, no occurrence of c.250G>A in individuals affected with Tuberous Sclerosis Complex has been reported. At least one publication reports experimental evidence evaluating an impact on protein function (example, Hoogeveen-Westerveld_2011). These results showed no damaging effect of this variant on both the formation and activity of the TSC1-TSC2 complex in an experimental system using immunoblotting followed by infrared scanner based detection. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Genome-Nilou Lab	RCV000234434	SCV002040514	benign	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000163475	SCV002528873	benign	Hereditary cancer-predisposing syndrome	2020-07-21	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV002512056	SCV002821978	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	TSC1: BP4, BS1
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000122183	SCV004221390	benign	not specified	2022-10-08	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. Computational tools predict this amino acid change may be benign. This variant has been seen where an alternate explanation for disease was also identified.
Color Diagnostics, LLC DBA Color Health	RCV000234434	SCV004360835	benign	Tuberous sclerosis 1	2022-05-17	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV002512056	SCV005225990	likely benign	not provided		criteria provided, single submitter	not provided
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000234434	SCV005881402	benign	Tuberous sclerosis 1	2025-02-01	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC1)	RCV000042223	SCV000066009	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
ITMI	RCV000122183	SCV000086400	not provided	not specified	2013-09-19	no assertion provided	reference population