Submissions for variant NM_000368.5(TSC1):c.2672dup (p.Asn891fs)

dbSNP: rs118203724

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000550474	SCV000641590	pathogenic	Tuberous sclerosis 1	2021-08-16	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050). This variant has been observed in individuals affected with tuberous sclerosis complex (PMID: 9328481, 9803264, 9863590, 10363127). This variant is also known as 2887insA and 2887_2888insA in the literature. ClinVar contains an entry for this variant (Variation ID: 48989). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn891Lysfs*13) in the TSC1 gene. It is expected to result in an absent or disrupted protein product.
Ambry Genetics	RCV001016278	SCV001177216	pathogenic	Hereditary cancer-predisposing syndrome	2019-04-03	criteria provided, single submitter	clinical testing	The c.2672dupA pathogenic mutation, located in coding exon 19 of the TSC1 gene, results from a duplication of A at nucleotide position 2672, causing a translational frameshift with a predicted alternate stop codon (p.N891Kfs*13). This alteration has been identified in multiple individuals diagnosed with tuberous sclerosis and has been reported as 2887insA and 2887-2888insA in the literature (Jones AC et al. Hum. Mol. Genet., 1997 Nov;6:2155-61; Young JM et al. Ann. Hum. Genet., 1998 May;62:203-13; Ali JB et al. J. Med. Genet., 1998 Dec;35:969-72; Dabora SL et al. Ann. Hum. Genet., 1998 Nov;62:491-504). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab	RCV000550474	SCV002040697	pathogenic	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000042240	SCV004848075	pathogenic	Tuberous sclerosis syndrome	2019-02-01	criteria provided, single submitter	clinical testing	The p.Asn891fs variant in TSC1 has been reported in 5 individuals with tuberous sclerosis (Jones 1997, Ali 1998, Young 1998) and was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 891 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the TSC1 gene is an established disease mechanism in individuals with tuberous sclerosis. In summary, this variant meets criteria to be classified as pathogenic for tuberous sclerosis in an autosomal dominant manner based upon predicted impact to the protein.
Myriad Genetics, Inc.	RCV000550474	SCV005897803	pathogenic	Tuberous sclerosis 1	2024-11-21	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21811971, 36232477].
Oasi Research Institute-IRCCS	RCV000550474	SCV005903210	pathogenic	Tuberous sclerosis 1		criteria provided, single submitter	research	The genomic variant c.2672dupA is a frameshift mutation resulting from the duplication of a single nucleotide.This variant creates a premature translational stop signal and is expected to result in a protein truncation or nonsense-mediated decay. ACMG criteria: PVS1 (LOF), PP4 (phenotype match), PM2 (absent from controls), PP3 (in silico evidence), PS2 (de novo)= Pathogenic. Based on the evidence outlined above, the variant was classified as Pathogenic.
Tuberous sclerosis database (TSC1)	RCV000042240	SCV000066026	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University	RCV000550474	SCV001370509	pathogenic	Tuberous sclerosis 1	2020-06-09	no assertion criteria provided	clinical testing