Submissions for variant NM_000548.5(TSC2):c.268C>T (p.Gln90Ter)

dbSNP: rs45517099

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000381969	SCV000329780	pathogenic	not provided	2023-01-20	criteria provided, single submitter	clinical testing	Identified in patients with tuberous sclerosis complex referred for genetic testing at GeneDx and in published literature (Choy 1999, Au 2007); Nonsense 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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 10735580, 25525159, 12111193, 16981987, 11112665, 25782670, 20633017, 17536269, 15798777, 20498439, 17304050, 32211034)
Ambry Genetics	RCV000491603	SCV000579585	pathogenic	Hereditary cancer-predisposing syndrome	2020-10-23	criteria provided, single submitter	clinical testing	The p.Q90* pathogenic mutation (also known as c.268C>T), located in coding exon 3 of the TSC2 gene, results from a C to T substitution at nucleotide position 268. This changes the amino acid from a glutamine to a stop codon within coding exon 3. This alteration has been reported in multiple unrelated individuals with clinical diagnoses of tuberous sclerosis complex (TSC) (Choy YS et al. Ann Hum Genet. 1999; 63(Pt 5):383-91; Langkau N et al. Eur J Pediatr. 2002; 161(7):393-402; Hung CC et al. BMC Med Genet. 2006; 7:72). 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.
Athena Diagnostics Inc	RCV000381969	SCV000615894	pathogenic	not provided	2017-07-31	criteria provided, single submitter	clinical testing
Invitae	RCV000707342	SCV000836434	pathogenic	Tuberous sclerosis 2	2023-05-15	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: 49738). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 10735580, 11112665, 12111193, 16981987, 17536269, 20498439, 20633017). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln90*) in the TSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050).
Baylor Genetics	RCV000707342	SCV001520799	pathogenic	Tuberous sclerosis 2	2020-03-17	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000707342	SCV002040911	pathogenic	Tuberous sclerosis 2	2021-11-07	criteria provided, single submitter	clinical testing
Tuberous sclerosis database (TSC2)	RCV000043003	SCV000066801	not provided	Tuberous sclerosis syndrome		no assertion provided	curation
deCODE genetics, Amgen	RCV000707342	SCV004022273	likely pathogenic	Tuberous sclerosis 2	2023-07-21	no assertion criteria provided	research	The variant NM_000548.5:c.268C>T (chr16:2053384) in TSC2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic.