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

gnomAD frequency: 0.00005  dbSNP: rs45517333

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001082570	SCV000262032	benign	Tuberous sclerosis 2	2025-02-02	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	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.
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; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2	2021-03-30	criteria provided, single submitter	clinical testing	TSC2 NM_000548 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
CeGaT Center for Human Genetics Tuebingen	RCV000034657	SCV001747145	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing	TSC2: BS2
Genome-Nilou Lab	RCV001082570	SCV002039840	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000566784	SCV002533516	likely benign	Hereditary cancer-predisposing syndrome	2021-02-03	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000606975	SCV004221456	likely benign	not specified	2023-07-19	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population (http://gnomad.broadinstitute.org) is higher than would generally be expected for pathogenic variants in this gene. This variant has been seen where an alternate explanation for disease was also identified. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive (PMID: 21309039).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000034657	SCV004563312	likely benign	not provided	2023-01-24	criteria provided, single submitter	clinical testing
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
GenomeConnect - Invitae Patient Insights Network	RCV001082570	SCV004228852	not provided	Tuberous sclerosis 2		no assertion provided	phenotyping only	Variant interpreted as Benign and reported on 05-23-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004534723	SCV004741320	likely benign	TSC2-related disorder	2023-03-15	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).