ClinVar Miner

Submissions for variant NM_000368.5(TSC1):c.2818C>T (p.Gln940Ter)

dbSNP: rs1588290078
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001016672 SCV001177652 pathogenic Hereditary cancer-predisposing syndrome 2023-01-06 criteria provided, single submitter clinical testing The p.Q940* pathogenic mutation (also known as c.2818C>T), located in coding exon 20 of the TSC1 gene, results from a C to T substitution at nucleotide position 2818. This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TSC1-related disease (Ogórek B et al. Genet Med 2020 Sep;22(9):1489-1497). This changes the amino acid from a glutamine to a stop codon within coding exon 20. 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.
Division of Medical Genetics, University of Washington RCV001250431 SCV001424798 likely pathogenic Tuberous sclerosis 1 2019-08-01 criteria provided, single submitter clinical testing This variant creates a premature termination codon. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of TSC1 is an established mechanism of disease for TSC (Young 1998, Sancak 2005, Au 2007). To our knowledge, this variant has not been previously reported in the literature. This variant is not present in population databases (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as likely pathogenic.
Genome-Nilou Lab RCV001250431 SCV002040642 pathogenic Tuberous sclerosis 1 2021-11-07 criteria provided, single submitter clinical testing
Invitae RCV001250431 SCV002232917 pathogenic Tuberous sclerosis 1 2022-07-05 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 821847). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 32461669). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln940*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002307655 SCV002600396 likely pathogenic Tuberous sclerosis syndrome 2022-10-10 criteria provided, single submitter clinical testing Variant summary: TSC1 c.2818C>T (p.Gln940X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251452 control chromosomes. c.2818C>T has been reported in the literature in individuals affected with Tuberous Sclerosis Complex (Ogrek_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.

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