ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1081C>G (p.Leu361Val) (rs796053483)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000189974 SCV000243645 likely pathogenic not provided 2014-02-19 criteria provided, single submitter clinical testing p.Leu361Val (CTG>GTG): c.1081 C>G in exon 11 of the TSC2 gene (NM_000548.3) A Leu361Val variant that is likely pathogenic has been identified in the TSC2 gene. The Leu361Val variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. A different amino acid substitution at this same position (Leu361Pro) has been previously reported as a de novo mutation in a patient with tuberous sclerosis (Choy et al., 1999). This substitution occurs at a position that is conserved across species. However, the Leu361Val variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in EPILEPSY panel(s).
Liping Wei Laboratory,Peking University RCV000754678 SCV000804770 likely pathogenic Autism spectrum disorder 2018-08-01 criteria provided, single submitter research
Invitae RCV000812345 SCV000952656 uncertain significance Tuberous sclerosis 2 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 361 of the TSC2 protein (p.Leu361Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual with epilepsy and neurodevelopmental disorders (PMID: 29655203) and an individual with clinical features of tuberous sclerosis (PMID: 30763456). ClinVar contains an entry for this variant (Variation ID: 207710). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C1). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 5

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