rs863223854
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5
The NM_003242.6(TGFBR2):c.1564G>A(p.Asp522Asn) 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. D522A) has been classified as Uncertain significance.
Frequency
Consequence
NM_003242.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFBR2 | NM_003242.6 | c.1564G>A | p.Asp522Asn | missense_variant | 7/7 | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.1564G>A | p.Asp522Asn | missense_variant | 7/7 | 1 | NM_003242.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 03, 2022 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 522 of the TGFBR2 protein (p.Asp522Asn). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Asp522 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been observed in individuals with TGFBR2-related conditions (Invitae), which suggests that this may be a clinically significant amino acid residue. 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 expected to disrupt TGFBR2 protein function. ClinVar contains an entry for this variant (Variation ID: 213936). This variant is also known as NM_001024847.2:c.1639G>A (p.Asp547Asn). This missense change has been observed in individual(s) with TGFBR2-related conditions (PMID: 17599521, 30675029, 34422331; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Medical Center Hamburg-Eppendorf | Nov 20, 2018 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 06, 2017 | The D522N variant of uncertain significance in the TGFBR2 gene has been reported in an individual with a clinical diagnosis of Loeys Dietz syndrome (LDS) and classic features (Lee et al., 2007); however, segregation information was not provided. This variant is not observed in large population cohorts (Lek et al., 2016). The D522N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Nevertheless, the D522N variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Finally, while missense variants in nearby residues (G520R, G520F, G520Y, W521R, D524N, D524Y) have been reported in HGMD in association with TGFBR2-related disorders (Stenson et al., 2014); the pathogenicity of these variants has not been definitively determined. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at