Submissions for variant NM_000548.5(TSC2):c.4225C>T (p.Arg1409Trp) (rs45517333)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001082570	SCV000262032	benign	Tuberous sclerosis 2	2019-12-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566784	SCV000675471	likely benign	Hereditary cancer-predisposing syndrome	2019-03-04	criteria provided, single submitter	clinical testing	Does not segregate with disease in family study (genes with incomplete penetrance);Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
GeneDx	RCV000606975	SCV000730310	benign	not specified	2017-04-25	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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768352	SCV000899058	uncertain significance	Lymphangiomyomatosis; Focal cortical dysplasia type II; Tuberous sclerosis 2	2018-06-29	criteria provided, single submitter	clinical testing	TSC2 NM_000548.4 exon 34 p.Arg1409Trp (c.4225C>T): This variant has not been reported in the literature but is present in 11/121418 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs45517333). This variant is present in ClinVar, with several labs classifying this variant as likely benign or benign (Variation ID: 41740). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Integrated Genetics/Laboratory Corporation of America	RCV000606975	SCV001338337	likely benign	not specified	2020-02-25	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.4225C>T (p.Arg1409Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.4e-05 in 239990 control chromosomes, predominantly at a frequency of 0.0001 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 slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in TSC2 causing Tuberous Sclerosis Complex phenotype (6.9e-05), suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.4225C>T has been reported in the literature in at least one individual affected with Tuberous Sclerosis Complex (Zarei_2002). This report does not provide unequivocal conclusions about association of the variant with Tuberous Sclerosis Complex. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Hoogeveen-Westerveld_2011). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign n=3; VUS n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Biesecker Lab/Clinical Genomics Section,National Institutes of Health	RCV000034657	SCV000043540	probably not pathogenic	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely benign.
Tuberous sclerosis database (TSC2)	RCV000054871	SCV000066340	not provided	Tuberous sclerosis syndrome		no assertion provided	curation