ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.734G>A (p.Arg245His)

gnomAD frequency: 0.00003  dbSNP: rs397515011
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000234531 SCV000285473 benign Tuberous sclerosis 2 2025-01-23 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV000248644 SCV000305257 likely benign not specified criteria provided, single submitter clinical testing
GeneDx RCV000248644 SCV000517897 likely benign not specified 2016-08-25 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.
Ambry Genetics RCV000570250 SCV000675566 likely benign Hereditary cancer-predisposing syndrome 2018-08-15 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.
Genome-Nilou Lab RCV000234531 SCV002041262 benign Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000570250 SCV002534102 likely benign Hereditary cancer-predisposing syndrome 2020-09-15 criteria provided, single submitter curation
Color Diagnostics, LLC DBA Color Health RCV000234531 SCV004360852 likely benign Tuberous sclerosis 2 2022-08-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000248644 SCV005075861 uncertain significance not specified 2024-04-02 criteria provided, single submitter clinical testing Variant summary: TSC2 c.734G>A (p.Arg245His) results in a non-conservative amino acid change located in the tuberin, N-terminal domain (IPR024584) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 249662 control chromosomes, predominantly at a frequency of 0.00016 within the East Asian subpopulation in the gnomAD database. Although this is higher than expected for a pathogenic variant in TSC2, there are less than 10 variant alleles present in this population, indicating it is possible that these occurrences may represent sequencing errors. Therefore, the available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.734G>A in individuals affected with Tuberous Sclerosis Complex has been reported. At least one publication reports experimental evidence evaluating an impact on protein function; these results showed no damaging effect of this variant (e.g, Hoogeveen-Westerveld_2013). The following publication has been ascertained in the context of this evaluation (PMID: 22903760). ClinVar contains an entry for this variant (Variation ID: 65021). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc. RCV000234531 SCV005404833 likely benign Tuberous sclerosis 2 2024-08-26 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
All of Us Research Program, National Institutes of Health RCV000055226 SCV005427050 likely benign Tuberous sclerosis syndrome 2024-09-27 criteria provided, single submitter clinical testing
Tuberous sclerosis database (TSC2) RCV000055226 SCV000083445 not provided Tuberous sclerosis syndrome no assertion provided curation

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