chr3-30691421-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5
The NM_003242.6(TGFBR2):c.1526G>T(p.Gly509Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,656 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. 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. G509D) has been classified as Uncertain significance.
Frequency
Consequence
NM_003242.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFBR2 | NM_003242.6 | c.1526G>T | p.Gly509Val | missense_variant, splice_region_variant | 7/7 | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.1526G>T | p.Gly509Val | missense_variant, splice_region_variant | 7/7 | 1 | NM_003242.6 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461656Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727142
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Feb 14, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 31, 2022 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 213935). This missense change has been observed in individuals with thoracic aortic aneurysm and dissection (PMID: 33824467; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 509 of the TGFBR2 protein (p.Gly509Val). - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 23, 2022 | 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: 33824467, 21949523) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 15, 2016 | Variant summary: The TGFBR2 c.1526G>T (p.Gly509Val) variant located in the protein kinase-like domain (via InterPro) causes a missense change involving a conserved nucleotide, which 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in one affected individual as a de novo event. A clinical diagnostic laboratory cites the variant as "pathogenic." In addition, other nearby TGFBR2 variants, Arg497Gln, Cys514Arg, and Ile510Ser, therefore suggesting the functional importance of this region. Taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance - Possibly Pathogenic," until additional information becomes available. - |
Isolated thoracic aortic aneurysm Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Department of Vascular Biology, Beijing Anzhen Hospital | Sep 01, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at