ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5238_5255del (p.His1746_Arg1751del) (rs137854218)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000013211 SCV000255914 pathogenic Tuberous sclerosis 2 2015-08-17 criteria provided, single submitter clinical testing
Invitae RCV000013211 SCV000544405 pathogenic Tuberous sclerosis 2 2018-07-21 criteria provided, single submitter clinical testing This sequence change deletes 18 nucleotides from exon 41 of the TSC2 mRNA (c.5238_5255delCATCAAGCGGCTCCGCCA). This leads to the deletion of 6 amino acid residues in the TSC2 protein (p.His1746_Arg1751del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has been reported in many individuals with tuberous sclerosis and found to be de novo in several sporadic cases (PMID: 10205261, 15874888, 15024740, 9829910, 11112665, 16114042, 21520333). Experimental studies have shown that this variant decreases TSC2 expression and activity in vitro (PMID: 21309039). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000483802 SCV000565634 pathogenic not provided 2018-04-03 criteria provided, single submitter clinical testing The c.5238_5255del18 pathogenic variant in the TSC2 gene has been reported multiple times inassociation with tuberous sclerosis (Beauchamp et al., 1998; van Eeghen et al., 2013; TSC2 LOVD).Additionally, functional studies indicate that c.5238_5255del18 translates an unstable protein and ispathogenic (Hoogeveen-Westerveld et al., 2011). This variant results in an in-frame deletion of 6amino acid residues, denoted p.H1746_R1751del, at a conserved position in the Rap-GAP domain ofthe TSC2 protein. The c.5238_5255del18 variant is not observed in large population cohorts (Lek etal., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server).
Ambry Genetics RCV000491359 SCV000579607 pathogenic Hereditary cancer-predisposing syndrome 2017-10-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Athena Diagnostics Inc RCV000483802 SCV000615924 pathogenic not provided 2015-08-17 criteria provided, single submitter clinical testing
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000043162 SCV000965684 pathogenic Tuberous sclerosis syndrome 2019-07-29 criteria provided, single submitter clinical testing
OMIM RCV000013211 SCV000033458 pathogenic Tuberous sclerosis 2 2003-05-01 no assertion criteria provided literature only
Tuberous sclerosis database (TSC2) RCV000043162 SCV000066527 not provided Tuberous sclerosis syndrome no assertion provided curation
Tuberous sclerosis database (TSC2) RCV000043162 SCV000066961 not provided Tuberous sclerosis syndrome no assertion provided curation
Tuberous sclerosis database (TSC2) RCV000055053 SCV000083271 not provided Lymphangiomyomatosis; Tuberous sclerosis syndrome no assertion provided curation

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