Submissions for variant NM_000548.5(TSC2):c.1378G>A (p.Ala460Thr)

gnomAD frequency: 0.00035  dbSNP: rs137854154

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130880	SCV000185785	benign	Hereditary cancer-predisposing syndrome	2015-08-20	criteria provided, single submitter	clinical testing	Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Co-occurence with mutation in same gene (phase unknown);General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Other data supporting benign classification
Invitae	RCV000989417	SCV000261891	benign	Tuberous sclerosis 2	2021-12-18	criteria provided, single submitter	clinical testing
Eurofins NTD LLC (GA)	RCV000122206	SCV000336111	likely benign	not specified	2015-10-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services,Illumina	RCV000042922	SCV000395580	likely benign	Tuberous sclerosis syndrome	2018-02-12	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Laboratory for Molecular Medicine,Mass General Brigham Personalized Medicine	RCV000122206	SCV000540600	benign	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.5% (46/8536) European chromosomes; ClinVar: 2 labs classify as LB. 3/5 pubs describe as nonpathogenic.
Mendelics	RCV000989417	SCV001139739	likely benign	Tuberous sclerosis 2	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000204918	SCV001150690	likely benign	not provided	2022-04-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000122206	SCV001748775	benign	not specified	2021-06-28	criteria provided, single submitter	clinical testing	Variant summary: TSC2 c.1378G>A (p.Ala460Thr) results in a non-conservative amino acid change located in the Tuberin, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0012 in 155816 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 18.11 fold of 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. To our knowledge, no occurrence of c.1378G>A in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV000204918	SCV001940283	benign	not provided	2018-11-08	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25281918, 25637381, 21309039, 24728327, 19258292, 27884173)
Genome-Nilou Lab	RCV000989417	SCV002041333	benign	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory,University of Chicago	RCV000122206	SCV002069942	likely benign	not specified	2021-10-07	criteria provided, single submitter	clinical testing
Sema4,Sema4	RCV000130880	SCV002532780	benign	Hereditary cancer-predisposing syndrome	2020-05-10	criteria provided, single submitter	curation
Tuberous sclerosis database (TSC2)	RCV000042922	SCV000066719	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
ITMI	RCV000122206	SCV000086427	not provided	not specified	2013-09-19	no assertion provided	reference population
CSER _CC_NCGL, University of Washington	RCV000042922	SCV000190665	likely benign	Tuberous sclerosis syndrome	2014-06-01	no assertion criteria provided	research
Biochemical Molecular Genetic Laboratory,King Abdulaziz Medical City	RCV000989417	SCV001190850	benign	Tuberous sclerosis 2	2020-02-05	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000122206	SCV001808527	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000122206	SCV001925923	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000122206	SCV001975849	benign	not specified		no assertion criteria provided	clinical testing