ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1281C>G (p.Ile427Met)

dbSNP: rs45478892
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463226 SCV000544504 uncertain significance Tuberous sclerosis 2 2023-10-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 427 of the TSC2 protein (p.Ile427Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of tuberous sclerosis complex (PMID: 22903760). ClinVar contains an entry for this variant (Variation ID: 64940). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TSC2 protein function. Experimental studies have shown that this missense change affects TSC2 function (PMID: 22903760). 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.
Ambry Genetics RCV001010730 SCV001170969 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-12 criteria provided, single submitter clinical testing The p.I427M variant (also known as c.1281C>G), located in coding exon 12 of the TSC2 gene, results from a C to G substitution at nucleotide position 1281. The isoleucine at codon 427 is replaced by methionine, an amino acid with highly similar properties. This alteration has been reported in at least one individual with suspected Tuberous sclerosis complex (Hoogeveen-Westerveld M et al. Hum Mutat, 2013 Jan;34:167-75). This variant was also reported in a cohort of patients with an autism spectrum disorder (Bahl S et al. Mol Autism, 2013 Mar;4:5). In one functional study, this alteration was found to have intermediate loss of the TSC1-TSC2 dependent inhibition of TORC1. (Hoogeveen-Westerveld M et al. Hum Mutat, 2013 Jan;34:167-75). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Genome-Nilou Lab RCV000463226 SCV002040600 uncertain significance Tuberous sclerosis 2 2021-11-07 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002490630 SCV002789950 uncertain significance Lymphangiomyomatosis; Isolated focal cortical dysplasia type II; Tuberous sclerosis 2 2022-05-31 criteria provided, single submitter clinical testing
Tuberous sclerosis database (TSC2) RCV000055143 SCV000083361 not provided Tuberous sclerosis syndrome no assertion provided curation

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