Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000548.5(TSC2):c.337-1G>A variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
TSC2 (HGNC:12363): (TSC complex subunit 2) This gene is a tumor suppressor gene that encodes the growth inhibitory protein tuberin. Tuberin interacts with hamartin to form the TSC protein complex which functions in the control of cell growth. This TSC protein complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.8, offset of 1, new splice context is: ctgtggcttttgtctttaAGgcg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-2054295-G-A is Pathogenic according to our data. Variant chr16-2054295-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 65038.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-2054295-G-A is described in Lovd as [Pathogenic]. Variant chr16-2054295-G-A is described in Lovd as [Pathogenic].
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute, Kanazawa Medical University
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Nov 07, 2021
Genome-Nilou Lab
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jul 30, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in TSC2 are known to be pathogenic (PMID: 10205261, 17304050). A different variant affecting this nucleotide (c.337-1G>T) has been reported in an individual affected with TSC (PMID: 10735580). This suggests that this nucleotide is important for normal RNA splicing, and that variants at this position may be pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been reported in an individual affected with tuberous sclerosis complex (TSC) (PMID: 23389244). This variant is also known as IVS3-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 65038). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 4 of the TSC2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
not provided Pathogenic:1
Dec 05, 2016
Athena Diagnostics
Significance: Pathogenic
Review Status: criteria provided, single submitter