rs104893816
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_003242.6(TGFBR2):c.1379G>A(p.Arg460His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,836 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. R460C) 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.1379G>A | p.Arg460His | missense_variant | 5/7 | ENST00000295754.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TGFBR2 | ENST00000295754.10 | c.1379G>A | p.Arg460His | missense_variant | 5/7 | 1 | NM_003242.6 | P1 | |
TGFBR2 | ENST00000359013.4 | c.1454G>A | p.Arg485His | missense_variant | 6/8 | 1 | |||
TGFBR2 | ENST00000672866.1 | n.2975G>A | non_coding_transcript_exon_variant | 5/7 | |||||
TGFBR2 | ENST00000673203.1 | n.257G>A | non_coding_transcript_exon_variant | 1/3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251464Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135906
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461836Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 727226
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jan 17, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 30, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 460 of the TGFBR2 protein (p.Arg460His). This variant is present in population databases (rs104893816, gnomAD 0.004%). This missense change has been observed in individuals with TGFBR2-related conditions (PMID: 16027248, 16885183, 18852674, 23884466, 25644172, 27508510). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12515). 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, 16799921, 19542084, 21098638, 21267002; 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 03, 2023 | The p.R460H variant (also known as c.1379G>A), located in coding exon 5 of the TGFBR2 gene, results from a G to A substitution at nucleotide position 1379. The arginine at codon 460 is replaced by histidine, an amino acid with highly similar properties. This variant has been found to segregate in multiple multigenerational families with syndromic and non-syndromic thoracic aortic aneurysm and dissection (TAAD) (Michaowska A et al. Pol Arch Internal Med, 2020 May; Pannu H et al. Circulation, 2005 Jul;112:513-20; Law C et al. J. Med. Genet., 2006 Dec;43:908-16). It has also been reported in several individuals with TAAD (Loeys BL et al. N. Engl. J. Med., 2006 Aug;355:788-98; Jawaid Y et al. Case Rep Cardiol, 2018 Dec;2018:8014820; Li J et al. Sci China Life Sci, 2019 Dec;62:1630-1637; Campens L et al. Orphanet J Rare Dis, 2015 Feb;10:9; Disabella E et al. Eur. J. Hum. Genet., 2006 Jan;14:34-8). Experimental studies indicate that this alteration affects TGFBR2 protein internalization and decreases TGFBR2 expression and signaling activity (Horbelt D et al. J. Cell. Sci., 2010 Dec;123:4340-50; Inamoto S et al. Cardiovasc. Res., 2010 Dec;88:520-9). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by BayesDel in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Loeys-Dietz syndrome 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jun 17, 2019 | The c.1454G>A (p.Arg485His) variant in the TGFBR2 gene has been reported in multiple unrelated families affected with Thoracic Aortic Aneurysm and Dissection (PMID 16027248,16251899, 16885183, 25644172) and segregates with disease in some of the families (PMID 16027248, 16885183). In vitro analysis showed this variant results in severely compromised internalization of the TGF-beta RII protein (PMID 21098638). Multiple in silico algorithms predicted this p.Arg485His change to be deleterious. Therefore, this c.1454G>A (p.Arg485His) variant in the TGFBR2 gene is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City | Jun 05, 2018 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 01, 2006 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 09, 2017 | The R460H mutation in the TGFBR2 gene has been reported multiple times in association with Marfan syndrome, TAAD, and related disorders (Pannu H et al., 2005; Disabella E et al., 2006; Law C et al., 2006). Pannu et al. identified R460H in two unrelated families and found this mutation co-segregated with a TAAD phenotype with reduced penetrance. Disabella et al. reported R460H in a 24 year-old female with aortic root dilation who met Ghent criteria for Marfan syndrome. She had a family history of sudden death in her father and paternal aunt (ages 37 and 45, respectively) due to aortic root dissection. Law et al. observed the R460H mutation in one large family with TAAD and a family history of sudden death. Postmortem autopsy on six individuals in this family identified ruptured aortic aneurysm and dissection as the cause of death. Furthermore, R460H was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Mutations at this residue (R460C, R460L) and in nearby residues (M457K, C461Y) have been reported in association with TAAD and other related disorders, supporting the functional importance of this residue and this region of the protein. Moreover, Pannu et al., suggests the R460 residue to be a mutation hot spot" for familial TAAD. Functional studies reported R460H exhibits a dominant-negative effect on extracellular signal-regulated kinase (ERK) and SMAD signaling which leads to a defect in TGF-B signaling (Horbelt D et al., 2010). In summary, R460H in the TGFBR2 gene is interpreted as a disease-causing mutation." - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at