ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.5024C>T (p.Pro1675Leu) (rs45483392)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000013201 SCV000544425 pathogenic Tuberous sclerosis 2 2019-08-19 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1675 of the TSC2 protein (p.Pro1675Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (rs45483392, ExAC no frequency). This variant has been reported in many individuals affected with tuberous sclerosis complex (TSC) (PMID: 9302281, 22867869, 11520734, 9463313, 12111193, 15024740, 21520333). In several individuals affected with TSC, this variant has been observed to arise de novo (PMID: 9302281, 10570911, 11112665, 21520333). This variant is also known as 5042C>T and P1657L in the literature. ClinVar contains an entry for this variant (Variation ID: 12393). Experimental studies have shown that this missense change decreases TSC2 protein expression levels, disrupts TSC2 phosphorylation, and prevents proper TSC2 protein binding with TSC1 (PMID: 22903760, 11290735). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000493720 SCV000583057 pathogenic not provided 2018-11-29 criteria provided, single submitter clinical testing The P1675L missense pathogenic variant has been reported previously in association with tuberous sclerosis complex (TSC) (Maheshwar et al., 1997; Dabora et al., 2001; TSC2 LOVD). Functional studies indicate that P1675L is damaging to the protein (Hoogeveen-Westerveld et al., 2013; Aicher et al., 2001). The P1675L variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution alters a conserved position predicted to be within the Rap-GAP domain of the TSC2 protein. Additionally, missense variants in a nearby residue (V1673F, V1673D) have been reported in the Human Gene Mutation Database in association with tuberous sclerosis (Stenson et al., 2014). Therefore, the presence of P1675L is consistent with a diagnosis of tuberous sclerosis in this individual.
Athena Diagnostics Inc RCV000493720 SCV000844589 pathogenic not provided 2015-09-30 criteria provided, single submitter clinical testing
OMIM RCV000013201 SCV000033448 pathogenic Tuberous sclerosis 2 1997-10-01 no assertion criteria provided literature only
Tuberous sclerosis database (TSC2) RCV000043065 SCV000066864 not provided Tuberous sclerosis syndrome no assertion provided curation
Tuberous sclerosis database (TSC2) RCV000055436 SCV000083657 not provided Lymphangiomyomatosis no assertion provided curation

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