ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5160+1G>A (rs45517399)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000201137 SCV000255910 pathogenic Tuberous sclerosis 2 2012-09-29 criteria provided, single submitter clinical testing
GeneDx RCV000485999 SCV000568294 pathogenic not provided 2017-02-20 criteria provided, single submitter clinical testing The c.5160+1 G>A splice site variant in the TSC2 gene has been reported multiple times previously reported in association with TSC (Dabora et al., 2001; Sancak et al., 2005; TSC2 LOVD). This pathogenic variant destroys the canonical splice donor site in intron 40, and is expected to cause abnormal gene splicing. The c.5160+1 G>A variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Invitae RCV000201137 SCV000826090 pathogenic Tuberous sclerosis 2 2018-05-03 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 40 of the TSC2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with tuberous sclerosis complex (PMID: 11112665). ClinVar contains an entry for this variant (Variation ID: 49425). 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. A different variant affecting this nucleotide (c.5160+1G>T) has been determined to be pathogenic (PMID: 27859028). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be 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). For these reasons, this variant has been classified as Pathogenic.
Tuberous sclerosis database (TSC2) RCV000042685 SCV000066480 not provided Tuberous sclerosis syndrome no assertion provided curation

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