Submissions for variant NM_000548.5(TSC2):c.5238_5255del (p.His1746_Arg1751del)

dbSNP: rs137854218

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000013211	SCV000544405	pathogenic	Tuberous sclerosis 2	2024-01-18	criteria provided, single submitter	clinical testing	This variant, c.5238_5255del, results in the deletion of 6 amino acid(s) of the TSC2 protein (p.His1746_Arg1751del), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with tuberous sclerosis (PMID: 9829910, 10205261, 11112665, 15024740, 15874888, 16114042, 21520333). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12402). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects TSC2 function (PMID: 21309039). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000483802	SCV000565634	pathogenic	not provided	2021-11-16	criteria provided, single submitter	clinical testing	In-frame deletion of 6 amino acids in a non-repeat region; Published functional studies demonstrate a damaging effect, with decreased TSC2 and TSC1 expression and increased S6K phosphorylation (Hoogeveen-Westerveld 2011); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 25782670, 5279523, 15121797, 30712878, 26540169, 26563443, 9829910, 22867869, 11112665, 15024740, 10607950, 12752578, 27406250, 29500070, 28397210, 28968464, 31370276, 31591157, 32313033, 32555378, 33942996, 32410215, 32320828, 32091432, 21309039)
Ambry Genetics	RCV000491359	SCV000579607	pathogenic	Hereditary cancer-predisposing syndrome	2018-11-08	criteria provided, single submitter	clinical testing	The c.5238_5255del18 pathogenic mutation (also known as p.H1746_R1751del) is located in coding exon 40 of the TSC2 gene. This pathogenic mutation results from an in-frame CATCAAGCGGCTCCGCCA deletion at nucleotide positions 5238 to 5255. This results in the in-frame deletion of six amino acids from codon 1746 to 1751. This deletion was originally reported in a sporadic case with tuberous sclerosis (Beauchamp RL et al. Hum. Mutat., 1998;12:408-16). Subsequently, this mutation (also reported as 5256del18bp and 1746delHIKRLR) has been identified in multiple patients with tuberous sclerosis (Jones AC et al. Am. J. Hum. Genet., 1999 May;64:1305-15; Dabora SL et al. Am. J. Hum. Genet., 2001 Jan;68:64-80; Au KS et al. Genet. Med., 2007 Feb;9:88-100). Furthermore, in vitro analysis showed that the mutant protein (reported as p.1746del6/1723del6) is unstable and increases T389-phosphorylated S6 kinase, thereby preventing the TSC-TSC2-dependent inhibition of the target of rapamycin complex 1 (TORC1) activity (Hoogeveen-Westerveld M et al. Hum. Mutat., 2011 Apr;32:424-35). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Athena Diagnostics	RCV000483802	SCV000615924	pathogenic	not provided	2023-08-14	criteria provided, single submitter	clinical testing	This variant appears to occur de novo in multiple individuals with clinical features associated with this gene. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Assessment of experimental evidence suggests this variant results in abnormal protein function. The variant decreases TSC2 expression and activity in vitro (PMID 21309039). The variant is located in a region that is considered important for protein function and/or structure.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000043162	SCV000965684	pathogenic	Tuberous sclerosis syndrome	2019-07-29	criteria provided, single submitter	clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000013211	SCV001423577	pathogenic	Tuberous sclerosis 2	2022-07-17	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000013211	SCV002022448	pathogenic	Tuberous sclerosis 2	2021-01-25	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000013211	SCV002041027	likely pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000483802	SCV002497866	pathogenic	not provided	2022-03-01	criteria provided, single submitter	clinical testing	TSC2: PM6:Strong, PM1, PM2, PM4, PP4, PS4:Supporting
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000013211	SCV002558008	pathogenic	Tuberous sclerosis 2	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with tuberous sclerosis-2 (MIM#613254). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Clinical symptoms can vary among affected individuals within the same family (PMID: 31018109). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported as pathogenic and de novo in multiple individuals with tuberous sclerosis complex (ClinVar, PMID: 32313033). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
3billion	RCV000013211	SCV002572890	pathogenic	Tuberous sclerosis 2	2022-09-01	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Inframe deletion located in a nonrepeat region is predicted to change the length of the protein and disrupt normal protein function. Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 21309039). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 10205261, 11112665). The variant has been previously reported as assumed (i.e. paternity and maternity not confirmed) de novo in at least one similarly affected unrelated individual (PMID: 10205261). The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000012402 / PMID: 9829910/ 3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	RCV000013211	SCV003915608	pathogenic	Tuberous sclerosis 2	2022-05-05	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000483802	SCV003929402	pathogenic	not provided	2021-10-05	criteria provided, single submitter	clinical testing	PP4, PM2, PM4, PM6, PS3, PS4
Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	RCV000013211	SCV004034090	pathogenic	Tuberous sclerosis 2	2023-07-01	criteria provided, single submitter	research
Neuberg Centre For Genomic Medicine, NCGM	RCV000013211	SCV004047570	pathogenic	Tuberous sclerosis 2		criteria provided, single submitter	clinical testing	The inframe deletion variant c.5238_5255del (p.His1746_Arg1751del) in TSC2 gene has been reported previously in many individuals with tuberous sclerosis and found to be de novo in several sporadic cases (Rok et al. 2005). Experimental studies have shown that this variant decreases TSC2 expression and activity in vitro (Hoogeveen-Westerveld et al. 2011). The p.His1746_Arg1751del variant is novel (not in any individuals) in gnomAD Exomes and 1000 Genomes. This variant has been reported to the ClinVar database with conflicting interpretations of pathogenicity as Pathogenic/Likely Pathogenic. This p.His1746_Arg1751del causes deletion of amino acid Histidine at position 1746 and deletion of amino acid Arginine at position 1751. For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000013211	SCV000033458	pathogenic	Tuberous sclerosis 2	2003-05-01	no assertion criteria provided	literature only
Tuberous sclerosis database (TSC2)	RCV000043162	SCV000066527	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Tuberous sclerosis database (TSC2)	RCV000043162	SCV000066961	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Tuberous sclerosis database (TSC2)	RCV000055053	SCV000083271	not provided	Lymphangiomyomatosis; Tuberous sclerosis syndrome		no assertion provided	curation