rs397515241
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3_ModeratePP5
The NM_000548.5(TSC2):c.2113G>A(p.Val705Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V705E) has been classified as Pathogenic.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:3
PS3, PM2 -
This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with TSC (PMID: 29101226 (2017), 22903760 (2012)). A functional study reported this variant as damaging to protein function (PMID: 22903760 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. -
Published functional studies demonstrate a damaging effect on TSC1-TSC2 complex formation (PMID: 22903760); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29101226, 22903760, 22867869) -
Tuberous sclerosis 2 Pathogenic:2Uncertain:1
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This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 705 of the TSC2 protein (p.Val705Met). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with tuberous sclerosis complex (PMID: 22903760, 29101226). ClinVar contains an entry for this variant (Variation ID: 65328). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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. -
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Hereditary cancer-predisposing syndrome Pathogenic:1
The p.V705M variant (also known as c.2113G>A), located in coding exon 19 of the TSC2 gene, results from a G to A substitution at nucleotide position 2113. The valine at codon 705 is replaced by methionine, an amino acid with highly similar properties. An in vitro functional assay showed that this variant is deleterious compared to wild-type (Hoogeveen-Westerveld M et al. Hum Mutat 2013 Jan;34(1):167-75). This alteration has been observed in at least one individual with a personal and/or family history that is consistent with TSC2-related disease (Personal communication). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Tuberous sclerosis syndrome Other:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at