Submissions for variant NM_000368.5(TSC1):c.3112AGC[7] (p.Ser1043dup)

dbSNP: rs2234980

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001080890	SCV000284717	benign	Tuberous sclerosis 1	2024-02-01	criteria provided, single submitter	clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV001080890	SCV001430707	likely benign	Tuberous sclerosis 1	2020-07-10	criteria provided, single submitter	clinical testing
GeneDx	RCV000034610	SCV001860152	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824583	SCV002074363	benign	not specified	2022-01-20	criteria provided, single submitter	clinical testing	Variant summary: TSC1 c.3127_3129dupAGC (p.Ser1043dup) results in an in-frame duplication of one serine residue that expands a repeat consisting of 6 serines to 7. The variant allele was found at a frequency of 0.00064 in 245184 control chromosomes (gnomAD). The observed variant frequency is approximately 25 fold of the estimated maximal expected allele frequency for a pathogenic variant in TSC1 causing Tuberous Sclerosis Complex phenotype (2.5e-05), strongly suggesting that the variant is benign. The variant, c.3127_3129dupAGC, has been reported in the literature in 2 Japanese individuals affected with Tuberous Sclerosis Complex, however, at least one of these individuals was noted to carry a co-occurring nonsense mutation, which could explain the phenotype, in addition the variant was also found in 3/100 healthy Japanese controls (Pipo_2000). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as benign (n=2) and likely benign(n=1). Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV002255261	SCV002531423	benign	Hereditary cancer-predisposing syndrome	2020-02-24	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000034610	SCV002585094	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	TSC1: BS1
Ambry Genetics	RCV002255261	SCV002607963	benign	Hereditary cancer-predisposing syndrome	2020-08-07	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000034610	SCV004221393	benign	not provided	2023-08-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001080890	SCV004360797	benign	Tuberous sclerosis 1	2022-09-30	criteria provided, single submitter	clinical testing
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000034610	SCV000043506	probably not pathogenic	not provided	2012-07-13	no assertion criteria provided	research	Converted during submission to Likely benign.
Tuberous sclerosis database (TSC1)	RCV000054843	SCV000066054	not provided	Tuberous sclerosis syndrome		no assertion provided	curation