3-30674228-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_003242.6(TGFBR2):c.1378C>T(p.Arg460Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,838 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 Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R460H) has been classified as Pathogenic.
Frequency
Consequence
NM_003242.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TGFBR2 | NM_003242.6 | c.1378C>T | p.Arg460Cys | missense_variant | 5/7 | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.1378C>T | p.Arg460Cys | missense_variant | 5/7 | 1 | NM_003242.6 | P1 | |
TGFBR2 | ENST00000359013.4 | c.1453C>T | p.Arg485Cys | missense_variant | 6/8 | 1 | |||
TGFBR2 | ENST00000672866.1 | n.2974C>T | non_coding_transcript_exon_variant | 5/7 | |||||
TGFBR2 | ENST00000673203.1 | n.256C>T | non_coding_transcript_exon_variant | 1/3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727230
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 10, 2022 | Reported in multiple individuals with familial thoracic aortic aneurysm and dissection (TAAD) and in individuals who met diagnostic criteria for Marfan syndrome (Pannu et al., 2005; Singh et al., 2006; Tran-Fadulu et al., 2009); Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies and in vitro assays have demonstrated that R460C affects protein trafficking, exhibits a dominant-negative effect, and fails to induce extracellular signal-regulated kinase (ERK) signaling activity (Horbelt et al., 2010).; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21267002, 25644172, 19159394, 16251899, 27508510, 16799921, 23685554, 23276923, 28152038, 16027248, 19542084, 21098638) - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Loeys-Dietz syndrome 2 Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 26, 2005 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 28, 2023 | This variant has been reported in multiple individuals with thoracic aortic aneurysm and dissection (TAAD), and it has been reported to co-segregate with TAAD in multiple families (PMID: 16799921, 16027248, 19159394, 19542084). This variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). It is predicted to be deleterious by in silico analysis. Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 21098638). A different missense substitution at this amino acid residue, p.Arg460His, has been previously reported in individuals with TAAD and Loeys-Dietz syndrome, and it is classified as pathogenic (ClinVar variation ID 12515), which supports the functional importance of this position. - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 04, 2023 | This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 460 of the TGFBR2 protein (p.Arg460Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with TGFBR2-related disease (PMID: 16027248, 16799921, 19159394, 19542084). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12514). 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 with a positive predictive value of 95%. Experimental studies have shown that this missense change affects TGFBR2 function (PMID: 21098638). This variant disrupts the p.Arg460 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16027248, 16251899, 21267002, 25644172, 27508510; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Cardiovascular phenotype Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 04, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at