ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.275A>T (p.Glu92Val) (rs137853994)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130758 SCV000185649 benign Hereditary cancer-predisposing syndrome 2018-12-18 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification;Subpopulation frequency in support of benign classification
GeneDx RCV000122217 SCV000243626 likely benign not specified 2018-02-27 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.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000122217 SCV000270956 likely benign not specified 2015-08-06 criteria provided, single submitter clinical testing p.Glu92Val in exon 4 of TSC2. This variant is not expected to have clinical sign ificance because it has been identified in 0.34% (61/18010) of European chromoso mes by the Exome Aggregation Consortium (ExAC,; d bSNP rs137853994).
Invitae RCV000989412 SCV000285313 benign Tuberous sclerosis 2 2019-12-31 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000122217 SCV000305186 likely benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000043383 SCV000395556 benign Tuberous sclerosis syndrome 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.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000122217 SCV000703518 benign not specified 2016-12-27 criteria provided, single submitter clinical testing
Mendelics RCV000989412 SCV001139734 likely benign Tuberous sclerosis 2 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000122217 SCV001338115 likely benign not specified 2020-01-27 criteria provided, single submitter clinical testing Variant summary: TSC2 c.275A>T (p.Glu92Val) results in a non-conservative amino acid change located in the N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.001 in 213250 control chromosomes (gnomAD). The observed variant frequency is approximately 14.6- fold the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), strongly suggesting that the variant is benign. c.275A>T has been reported in the literature in individuals affected with Tuberous Sclerosis Complex (examples-Dunlop_2011, Bullich_2018) and in at least one unaffected family member (Dunlop_2011). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Dunlop_2011). Seven ClinVar submitters (evaluation after 2014) classified the variant as benign (n=2)/likely benign (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Tuberous sclerosis database (TSC2) RCV000043383 SCV000067189 not provided Tuberous sclerosis syndrome no assertion provided curation
ITMI RCV000122217 SCV000086438 not provided not specified 2013-09-19 no assertion provided reference population

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