rs1057520642
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000548.5(TSC2):c.1889G>A(p.Gly630Asp) 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. G630S) has been classified as Uncertain significance.
Frequency
Consequence
NM_000548.5 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC2 | NM_000548.5 | c.1889G>A | p.Gly630Asp | missense_variant | 18/42 | ENST00000219476.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC2 | ENST00000219476.9 | c.1889G>A | p.Gly630Asp | missense_variant | 18/42 | 5 | NM_000548.5 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 32
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Tuberous sclerosis 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 08, 2017 | In summary, this variant has uncertain impact on TSC2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with a TSC2-related disease. ClinVar contains an entry for this variant (Variation ID: 379559). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with aspartic acid at codon 630 of the TSC2 protein (p.Gly630Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 06, 2021 | The p.G630D variant (also known as c.1889G>A), located in coding exon 17 of the TSC2 gene, results from a G to A substitution at nucleotide position 1889. The glycine at codon 630 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with TSC2-related disease (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 27, 2017 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 14, 2017 | The G630D variant has not been published as a pathogenic variant, nor has it been reported as abenign variant to our knowledge. The G630D variant is not observed in large population cohorts (Leket al., 2016). The G630D variant is a non-conservative amino acid substitution, which is likely toimpact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a position that is conserved across species, and in silico analysispredicts this variant is probably damaging to the protein structure/function. In summary, based on thecurrently available information, it is unclear whether this variant is a pathogenic variant or a rarebenign variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at