ClinVar Miner

Submissions for variant NM_000368.4(TSC1):c.1526G>A (p.Arg509Gln) (rs118203543)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000122191 SCV000243462 benign not specified 2017-09-12 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.
Invitae RCV000464379 SCV000562474 benign Tuberous sclerosis 1 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567091 SCV000675388 likely benign Hereditary cancer-predisposing syndrome 2018-03-22 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Subpopulation frequency in support of benign classification;In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000122191 SCV001362453 benign not specified 2019-02-08 criteria provided, single submitter clinical testing Variant summary: TSC1 c.1526G>A (p.Arg509Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 276324 control chromosomes, predominantly at a frequency of 0.002 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 80 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 found primarily in populations of African origin. c.1526G>A has been reported in the literature in a child of African origin with multiple congenital malformations and no signs of Tuberous Sclerosis Complex (TSC); the variant was also identified in one of the parents (no signs of TSC). Experimental evidence evaluating an impact on protein function demonstrated the variant to display similar values to the wild type and be active in immunoblotting assay and to not affect TSC1 function (Hoogeveen-Westerveld_2011, Nellist_2009). Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as benign (2x) and once as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Tuberous sclerosis database (TSC1) RCV000042044 SCV000065827 not provided Tuberous sclerosis syndrome no assertion provided curation
ITMI RCV000122191 SCV000086409 not provided not specified 2013-09-19 no assertion provided reference population

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