ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1839+6G>A (rs45517204)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000233074 SCV000285258 benign Tuberous sclerosis 2 2018-01-12 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000349195 SCV000342015 likely benign not specified 2016-06-23 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000042920 SCV000395593 uncertain significance Tuberous sclerosis syndrome 2016-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000349195 SCV000515024 benign not specified 2015-03-13 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.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000513698 SCV000610731 likely benign not provided 2017-05-11 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000233074 SCV000782400 uncertain significance Tuberous sclerosis 2 2016-11-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000349195 SCV000918334 benign not specified 2018-11-23 criteria provided, single submitter clinical testing Variant summary: TSC2 c.1839+6G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00044 in 276158 control chromosomes, predominantly at a frequency of 0.0009 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), while the overall frequency of the variant is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant; these data strongly suggest that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.1839+6G>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with other pathogenic variants have been reported (TSC2 c.2968_2971dupAGGA, p.Ile991Lysfs*16; TSC2 c.2590C>T, p.Gln864*) (LOVD (Tuberous sclerosis database)), providing supporting evidence for a benign role. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign (4x) and twice as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Tuberous sclerosis database (TSC2) RCV000042920 SCV000066716 not provided Tuberous sclerosis syndrome no assertion provided curation

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