ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.250G>A (p.Ala84Thr) (rs118203357)

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Total submissions: 10
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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 In silico models in agreement (benign);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification;Subpopulation frequency in support of benign classification
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000122183 SCV000230916 benign not specified 2015-03-19 criteria provided, single submitter clinical testing
Invitae RCV000234434 SCV000284703 benign Tuberous sclerosis 1 2020-12-01 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics 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 Clinical Services Laboratory,Illumina RCV001167327 SCV001329808 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.
Illumina Clinical Services Laboratory,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.
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

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