rs727503477
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_003242.6(TGFBR2):c.1591G>A(p.Ala531Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,858 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. A531D) has been classified as Likely pathogenic.
Frequency
Consequence
NM_003242.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFBR2 | NM_003242.6 | c.1591G>A | p.Ala531Thr | missense_variant | 7/7 | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.1591G>A | p.Ala531Thr | missense_variant | 7/7 | 1 | NM_003242.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461858Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727238
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:2Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 25, 2023 | 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. 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: 165399). This missense change has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 24793577). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 531 of the TGFBR2 protein (p.Ala531Thr). - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 08, 2023 | This missense variant replaces alanine with threonine at codon 531 of the TGFBR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with thoracic aortic aneurysm and aortic dissection (TAAD) and segregated with TAAD and/or features of Loeys-Dietz syndrome in 5 affected relatives including two obligate carriers (ClinVar submission ID: SCV000200581.5). This variant has also been reported in an additional unrelated individual with Loeys-Dietz syndrome (PMID: 32887874) and in an individual suspected of having TAAD, Loeys-Dietz syndrome or Marfan syndrome (PMID: 24793577). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 02, 2023 | The p.A531T variant (also known as c.1591G>A), located in coding exon 7 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1591. The alanine at codon 531 is replaced by threonine, an amino acid with similar properties, and is located in the kinase domain. This variant has been detected in a cohort suspected of having Marfan syndrome, Loeys-Dietz syndrome (LDS) or thoracic aortic aneurysm and dissection (TAAD), and segregated with TAAD and/or features of LDS in several members of one family (Lerner-Ellis JP et al. Mol. Genet. Metab., 2014 Jun;112:171-6; external lab pers. comm.). This variant has also been detected in additional individuals with TAAD (Ambry internal data). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Tebben AJ et al. Acta Crystallogr D Struct Biol. 2016 05;72(Pt 5):658-74). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Loeys-Dietz syndrome 2 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 05, 2024 | The c.1591G>A (p.Ala531Thr) variant in the TGFBR2 gene that encodes for transforming growth factor beta receptor 2, has been identified in individuals affected with TGFR2-related conditions including thoracic aortic aneurysm and dissection (TAAD), spontaneous coronary artery dissection, aneurysm and Loeys-Dietz syndrome (PMID: 24793577, 32887874, 36103205) and segregated with familial TAAD and/or features of Loeys-Dietz syndrome (ClinVar [ID: 165399, Accession: SCV000200581]). In-silico computational prediction tools suggest that the p.Ala531Thr variant may have deleterious effect on the protein function (REVEL score: 0.837).This variant is found to be absent in the general population database, gnomAD. ClinVar has an entry for this variant (ID: 165399). Therefore, the c.1591G>A (p.Ala531Thr) variant in the TGFBR2 gene is classified as likely pathogenic. - |
TGFBR2-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 21, 2023 | The TGFBR2 c.1591G>A variant is predicted to result in the amino acid substitution p.Ala531Thr. This variant was reported in two patients with Loeys-Dietz syndrome (Table S1, Lerner-Ellis. 2014. PubMed ID: 24793577; Saw. 2020. PubMed ID: 32887874). This variant is listed in ClinVar as uncertain and likely pathogenic, and was reported to segregate with TAAD and/or Loeys-Dietz syndrome in six family members undergoing testing in a different laboratory (https://www.ncbi.nlm.nih.gov/clinvar/variation/165399/). This variant is interpreted as likely pathogenic. - |
Loeys-Dietz syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 19, 2014 | The Ala531Thr variant in TGFBR2 has been identified by our laboratory in 1 white individual with familial thoracic aortic aneurysm and dissection (familial TAAD ) and segregated with familial TAAD and/or features of Loeys Dietz syndrome in 5 affected relatives including two obligate carriers. It was absent from large po pulation studies. Computational prediction tools and conservation analysis sugge st that the Ala531Thr variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, although addition al studies are required to fully establish its clinical significance, the Ala531 Thr variant is classified as likely pathogenic based on the segregation data. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 27, 2022 | Identified in an individual with suspected Loeys-Dietz syndrome and in an individual with spontaneous coronary artery dissection, however segregation and detailed clinical information were not provided in either case (Lerner-Ellis et al., 2014; Saw et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32887874, 24793577) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at