Submissions for variant NM_000548.5(TSC2):c.774+1G>A (rs45517128)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000423250	SCV000520880	pathogenic	not provided	2017-01-03	criteria provided, single submitter	clinical testing	The c.774+1 G>A splice site variant in the TSC2 gene has been previously reported in association with TSC (Sancak et al., 2005; Au et al., 2007; TSC2 LOVD). This pathogenic variant destroys the canonical splice donor site in intron 8, and is expected to cause abnormal gene splicing. Additionally, the c.774+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	RCV001037395	SCV001200806	pathogenic	Tuberous sclerosis 2	2019-12-31	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 8 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). Disruption of this splice site has been observed in individual(s) with tuberous sclerosis complex (PMID: 10735580, 15798777, 17304050, 29101226). In at least one individual the splice site variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 49919). 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. 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)	RCV000043186	SCV000066986	not provided	Tuberous sclerosis syndrome		no assertion provided	curation

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