ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.721G>A (p.Val241Ile)

gnomAD frequency: 0.00002  dbSNP: rs200943828
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV001712292 SCV000532691 likely benign not provided 2019-06-05 criteria provided, single submitter clinical testing
Invitae RCV000554001 SCV000644661 benign Tuberous sclerosis 2 2023-12-24 criteria provided, single submitter clinical testing
Ambry Genetics RCV000572855 SCV000675575 likely benign Hereditary cancer-predisposing syndrome 2019-01-23 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Genome-Nilou Lab RCV000554001 SCV002041258 benign Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001797720 SCV002041597 likely benign not specified 2021-11-26 criteria provided, single submitter clinical testing Variant summary: TSC2 c.721G>A (p.Val241Ile) 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 5.2e-05 in 250168 control chromosomes (gnomAD v2.1 exomes dataset). This frequency is somewhat lower than the maximum expected for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), however in certain subpopulations the variant occurs with even higher allele frequencies, suggesting that it can be a benign polymorphism. To our knowledge, no occurrence of c.721G>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Three 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 (n=1) / likely benign (n=2). Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4 RCV000572855 SCV002534100 likely benign Hereditary cancer-predisposing syndrome 2021-06-27 criteria provided, single submitter curation

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