Submissions for variant NM_000368.5(TSC1):c.1998-2A>G

dbSNP: rs1057518217

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413689	SCV000491667	pathogenic	not provided	2025-01-13	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 29432982)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003323527	SCV004028631	likely pathogenic	Tuberous sclerosis syndrome	2023-07-14	criteria provided, single submitter	clinical testing	Variant summary: TSC1 c.1998-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250794 control chromosomes. To our knowledge, no occurrence of c.1998-2A>G in individuals affected with Tuberous Sclerosis Complex and no experimental evidence demonstrating its impact on protein function have been reported. One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003505107	SCV004330276	pathogenic	Tuberous sclerosis 1	2023-11-17	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 15 of the TSC1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individuals with clinical features of tuberous sclerosis complex (PMID: 29432982; Invitae). ClinVar contains an entry for this variant (Variation ID: 373102). 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.