rs376285784
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM5PP3
The NM_000548.5(TSC2):c.1514G>A(p.Arg505Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,696 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R505G) has been classified as Uncertain significance.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.1514G>A | p.Arg505Gln | missense_variant | 15/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.1514G>A | p.Arg505Gln | missense_variant | 15/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251260Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135854
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461494Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6AN XY: 727048
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152202Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Sep 14, 2023 | - - |
Tuberous sclerosis syndrome Uncertain:1Other:1
not provided, no classification provided | curation | Tuberous sclerosis database (TSC2) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jun 28, 2023 | This missense variant replaces arginine with glutamine at codon 505 of the TSC2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have reported that the variant demonstrated moderate impact on TSC2 stability, TSC1-TSC2 interaction, RhebGAP activity and mTORC1 pathway activation (PMID: 21407264, 22903760). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251260 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2019 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 18, 2023 | The p.R505Q variant (also known as c.1514G>A), located in coding exon 14 of the TSC2 gene, results from a G to A substitution at nucleotide position 1514. The arginine at codon 505 is replaced by glutamine, an amino acid with highly similar properties. This alteration has been identified in an individual with facial angiofibromas, seizures, and intellectual disability (ID), as well as this individual's mother with mild ID and maternal grandmother with no known features of tuberous sclerosis (Dunlop EA et al. Eur. J. Hum. Genet., 2011 Jul;19:789-95). Two functional studies have indicated that this alteration may result in partially reduced TORC1 inhibition (Dunlop EA et al. Eur. J. Hum. Genet., 2011 Jul;19:789-95; Hoogeveen-Westerveld M et al. Hum. Mutat., 2013 Jan;34:167-75). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at