ClinVar Genomic variation as it relates to human health

The TSC1 c.1525C>T (p.Arg509*) variant has been reported in the published literature in affected individuals with tuberous scelorosis complex (PMIDs: 9242607 (1997), 9328481 (1997), 9863590 (1998), 9924605 (1998), 16981987 (2006), 25900779 (2015), 32211034 (2020), 34403804 (2021), and 35918040 (2022)). It has also been reported in patients with epilepsy (PMIDs: 29655203 (2018) and 32655475 (2020)). A functional study demonstrated that this variant is damaging to protein function (PMID: 20547222 (2010)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic.

This variant is expected to result in the loss of a functional protein. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene.

Published functional studies demonstrate that R509X prevents TSC1 aggregation (Hoogeveen-Westerveld et al., 2010); Mosaic variant in a patient with TSC previously tested at GeneDx; 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: 25525159, 29642139, 29932062, 20547222, 9328481, 10533066, 11112665, 9924605, 25900779, 9242607, 28288225, 34426522, 29655203, 32211034, 32655475, 34403804, 34849272, 33826429, 28087349)

The variant is not observed in the gnomAD v2.1.1 dataset. This variant was predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000048796 / PMID: 9242607). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

TSC1 NM_000368.4 exon 15 p.Arg509* (c.1525C>T): This variant has been reported in the literature in several individuals with tuberous sclerosis (Ali 1998 PMID:9863590, Kwiatkowska 1998 PMID:9924605, Dabora 2001 PMID:11112665, Hung 2006 PMID:16981987, Hoogeveen-Westerveld 2010 PMID:20547222, Zhang 2015 PMID:25900779), including multiple entries in the Tuberous Sclerosis Database (http://chromium.lovd.nl/LOVD2/TSC/variants), with several of these entries reported to be de novo. This variant is not present in large control databases, but is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:48796). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. In vitro functional studies predict that this variant will impact the protein by impairing TSC1 aggregation (Hoogeveen-Westerveld 2010 PMID:20547222). However, these studies may not accurately represent in vivo biological function. This variant creates a premature stop at this codon which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Rosset 2017 PMID:28222202). In summary, this variant is classified as pathogenic based on the data above.

This sequence change creates a premature translational stop signal (p.Arg509*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with tuberous sclerosis complex (PMID: 9242607, 9863590, 9924605, 11112665, 16981987, 20547222, 21520333, 25900779). This variant is also known as 1746C>T. ClinVar contains an entry for this variant (Variation ID: 48796). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

The p.R509* pathogenic mutation (also known as c.1525C>T), located in coding exon 13 of the TSC1 gene, results from a C to T substitution at nucleotide position 1525. This changes the amino acid from an arginine to a stop codon within coding exon 13. The alteration has been reported in multiple individuals who met diagnostic criteria for tuberous sclerosis complex (TSC)(van Slegtenhorst M et al. Science, 1997 Aug;277:805-8; Zhang H et al. J. Hum. Genet., 1999;44:391-6; Zhang Y et al. Neuromolecular Med., 2015 Jun;17:202-8). 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.

PVS1, PS4, PM2, PP4

ACMG categories: PVS1,PS2,PM2,PP3,PP5

The TSC1 c.1525C>T variant is predicted to result in premature protein termination (p.Arg509*). This variant was reported in patients with Tuberous sclerosis (reported as 1746C>T, R509X in Table 1 in van Slegtenhorst et al. 1997. PubMed ID: 9242607; suppl. Table 2 in Bąbol-Pokora et al. 2021. PubMed ID: 34403804; Ng et al. 2022. PubMed ID: 35918040) and it occurred de novo in at least one patient (suppl. Table 1 in Ding et al. 2020. PubMed ID: 32211034 ). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in TSC1 are expected to be pathogenic. This variant is interpreted as pathogenic.

The variant NM_000368.5:c.1525C>T (chr9:132906053) in TSC1 was detected in 3 heterozygotes out of 58K WGS Icelanders (MAF= 0,003%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PM2, PP5_Strong) this variant classifies as likely pathogenic.