Submissions for variant NM_000368.5(TSC1):c.989dup (p.Ser331fs)

dbSNP: rs118203478

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000189866	SCV000243519	pathogenic	not provided	2022-08-22	criteria provided, single submitter	clinical testing	Reported previously multiple times (sometimes using alternative nomenclature 1210insT) in association with TSC (van Slegtenhorst et al., 1999; Zhang et al., 1999; TSC1 LOVD).; Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15798777, 31855466, 29655203, 25782670, 10570911, 23341583, 28968464, 10227394)
Athena Diagnostics Inc	RCV000201139	SCV000255870	pathogenic	Tuberous sclerosis 1	2014-07-09	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414909	SCV000492767	pathogenic	Renal insufficiency; Renal cortical cysts; Cortical dysplasia	2015-10-21	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491374	SCV000579945	pathogenic	Hereditary cancer-predisposing syndrome	2019-05-17	criteria provided, single submitter	clinical testing	The c.989dupT pathogenic mutation, located in coding exon 8 of the TSC1 gene, results from a duplication of T at nucleotide position 989, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in multiple individuals who met clinical criteria for tuberous sclerosis complex (TSC); this alteration is also referred to as 1210insT, 989insT, and c.990insT in the literature (van Slegtenhorst M et al. J Med Genet. 1999; 36(4):285-9; Zhang H et al. J Hum Genet. 1999; 44(6):391-6; Dunet V et al. BMJ Case Rep. 2013; 2013; Rosset C et al. PLoS ONE. 2017 Oct;12:e0185713). In addition to the clinical data presented in the literature, 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.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000201139	SCV000782383	pathogenic	Tuberous sclerosis 1	2016-11-01	criteria provided, single submitter	clinical testing
Invitae	RCV000201139	SCV000931870	pathogenic	Tuberous sclerosis 1	2023-08-05	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 49135). This variant is also known as c.990insT and c.1210insT. This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 10227394, 10570911, 23341583, 28968464). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser331Glufs*10) in the TSC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC1 are known to be pathogenic (PMID: 10227394, 17304050).
Mayo Clinic Laboratories, Mayo Clinic	RCV000189866	SCV001714331	pathogenic	not provided	2019-04-15	criteria provided, single submitter	clinical testing	PVS1, PS4_moderate, PM2, PP4
Genome-Nilou Lab	RCV000201139	SCV002041075	pathogenic	Tuberous sclerosis 1	2021-11-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000201139	SCV003806571	pathogenic	Tuberous sclerosis 1	2022-12-29	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Tuberous sclerosis database (TSC1)	RCV000042390	SCV000066180	not provided	Tuberous sclerosis syndrome		no assertion provided	curation