ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.4508A>C (p.Gln1503Pro) (rs45516293)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000492813 SCV000581956 pathogenic not provided 2018-10-23 criteria provided, single submitter clinical testing The Q1503P pathogenic variant in the TSC2 gene has been previously reported multiple times in association with TSC (Khare et al., 2001; Au et al., 2007). Functional studies indicate that Q1503P disrupts the function of the TSC1-TSC2 complex (Wentink et al., 2012; Hoogeveen-Westerveld et al., 2013). The Q1503P variant is not observed in large population cohorts (Lek et al., 2016). The Q1503P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. A different missense variant at the same residue as well as multiple missense variants in nearby residues have been reported in association with TSC (Stenson et al., 2014; TSC2 LOVD), supporting the functional importance of this region of the protein. Therefore, the presence of Q1503P is consistent with the diagnosis of TSC in this individual.
Invitae RCV000013210 SCV000644542 likely pathogenic Tuberous sclerosis 2 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 1503 of the TSC2 protein (p.Gln1503Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with mild manifestations of tuberous sclerosis complex (TSC) in two families from the same geographic area (PMID: 11403047). ClinVar contains an entry for this variant (Variation ID: 12401). Experimental in vitro studies have shown that this missense change inactivates the TSC1-TSC2 complex without disrupting TSC1-TSC2 binding, and increases the T389/S6K ratio (PMID: 22903760, 21332470). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000043266 SCV000697470 pathogenic Tuberous sclerosis syndrome 2017-07-28 criteria provided, single submitter clinical testing Variant summary: The TSC2 c.4508A>C (p.Gln1503Pro) variant involves the alteration of a conserved nucleotide that lies within the Rap GTPase activating protein domain (InterPro). 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120242 control chromosomes (ExAC and publication controls). The variant was identified in two families from the same geographical area with multiple affected individuals in each family. While the physical features typical of tuberous sclerosis were mild, affected individuals had significant neuropsychiatric symptoms including pervasive developmental disorder and autism. The variant cosegregated with disease completely in 14 affected and 9 unaffected individuals (Khare_JMG_2001). A functional study revealed the variant was unable to inhibit S6K phosphorylation in cultured cells (Wentink_Clin Genet_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Ambry Genetics RCV000720321 SCV000851198 pathogenic History of neurodevelopmental disorder 2016-08-12 criteria provided, single submitter clinical testing Strong segregation with disease (lod >3 = >10 meioses);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);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
OMIM RCV000013210 SCV000033457 pathogenic Tuberous sclerosis 2 2001-05-01 no assertion criteria provided literature only
Tuberous sclerosis database (TSC2) RCV000043266 SCV000067068 not provided Tuberous sclerosis syndrome no assertion provided curation
GeneReviews RCV000013210 SCV000245754 pathogenic Tuberous sclerosis 2 2015-09-03 no assertion criteria provided literature only

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