chr9-99149253-G-A
Variant summary
Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong
The NM_004612.4(TGFBR1):c.1460G>A(p.Arg487Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,028 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. R487W) has been classified as Pathogenic.
Frequency
Consequence
NM_004612.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 19 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TGFBR1 | NM_004612.4 | c.1460G>A | p.Arg487Gln | missense_variant | 9/9 | ENST00000374994.9 | NP_004603.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TGFBR1 | ENST00000374994.9 | c.1460G>A | p.Arg487Gln | missense_variant | 9/9 | 1 | NM_004612.4 | ENSP00000364133 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152028Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152028Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74252
ClinVar
Submissions by phenotype
Loeys-Dietz syndrome 1 Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | Oct 20, 2021 | ACMG classification criteria: PS2 strong, PS3 supporting, PS4 moderate, PM2 moderate, PM5, PP3 supporting - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 2006 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Nov 01, 2023 | PS4, PM1, PM2, PM5, PP3, PP5 - The variant has been reported in ClinVar as Pathogenic by other laboratories (Variation ID 527177). This variant has been previously reported as causative for Marfan syndrome. (PMID:25652356). - |
Pathogenic, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene. In addition, missense variants have been postulated to exert a dominant negative effect. Both mechanisms are associated with Loeys-Dietz syndrome (MIM#609192) (PMID: 30701076). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Several pathogenic variants have been reported for codons 486 and 487 (ClinVar, DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been identified in at least ten patients with Loeys-Dietz syndrome, with a single case of maternal mosaicism (Clinvar; PMID: 16928994, 16791849, 22113417, 25116393, 30219046). (SP) 1204 - This variant has been shown to be de novo in the proband (parental status not tested but assumed). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
Familial thoracic aortic aneurysm and aortic dissection Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 03, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 487 of the TGFBR1 protein (p.Arg487Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Loeys-Dietz syndrome (PMID: 16791849, 18455604; 22113417and23884466). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12525). 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 TGFBR1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TGFBR1 function (PMID: 21358634). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Arg487 amino acid residue in TGFBR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15731757, 16928994, 22414221, 23884466, 25110237). 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 | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 09, 2018 | The p.R487Q pathogenic mutation (also known as c.1460G>A), located in coding exon 9 of the TGFBR1 gene, results from a G to A substitution at nucleotide position 1460. The arginine at codon 487 is replaced by glutamine, an amino acid with highly similar properties, and is located in the protein kinase domain. This alteration has been reported in multiple individuals reported to have Loeys-Dietz syndrome (LDS) and related features (Loeys BL et al. N Engl J Med. 2006;355:788-98; Akutsu K et al. Circ J. 2007;71:1305-9; Melenovsky V et al. J Thorac Cardiovasc Surg. 2008;135:1174-5,1175.e1; Yang JH et al. J Hum Genet. 2012;57:52-6; Wang C et al. Chin Med J. 2014;127:2398-9; Ting TW et al. Eur J Pediatr. 2014;173(3):387-91; Pieroni A et al. Intern Emerg Med. 2015;10:165-70). In addition, this alteration was reported as a de novo occurrence in an individual with aortic dissection (Mátyás G et al. Hum Mutat. 2006;27:760-9), and has been reported to result in altered protein function (Goudie DR et al. Nat Genet. 2011;43:365-9). Other alterations affecting this amino acid (p.R487W, p.R487P, and p.R487G) have also been reported in association with LDS or detected in LDS cohorts (Loeys BL et al. N Engl J Med. 2006;355:788-98; Frischmeyer-Guerrerio PA et al. Sci Transl Med. 2013;5(195):195ra94). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | TGFBR1: PM1, PM2, PM5, PM6, PS4:Moderate, PP3, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 28, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies demonstrate reduced elastin and fibulin 1 expression, impaired deposition of elastic fibers, and impaired TGF-beta signaling (Barnett et al., 2011; Goudie et al., 2011); 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: 23884466, 27879313, 22113417, 21267002, 17061023, 24146167, 16928994, 18455604, 25116393, 17652900, 21358634, 29907982, 24931266, 30219046, 31915033, 32352226, 16791849) - |
Loeys-Dietz syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 26, 2019 | Variant summary: TGFBR1 c.1460G>A (p.Arg487Gln) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250796 control chromosomes (gnomAD). c.1460G>A has been reported in the literature, including de novo occurrences, in multiple individuals affected with Loeys-Dietz Syndrome, acute aortic dissection and thoracic aortic aneurysms (Loeys_2006, Matyas_2006, Akutsu_2007, Yang_2012). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant to result in decreased expression and impaired deposition of elastic fibers, while it also causes decreased TGF-beta signaling (Barnett_2011, Goudie_2011). Three ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
TGFBR1-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 14, 2024 | The TGFBR1 c.1460G>A variant is predicted to result in the amino acid substitution p.Arg487Gln. This variant has been reported in individuals with Loeys-Dietz syndrome type 1 and thoracic aortic aneurysms and dissections (TAAD) (Matyas et al. 2006. PubMed ID: 16791849; Melenovsky et al. 2008. PubMed ID: 18455604; Yang et al. 2011. PubMed ID: 22113417). This variant, in addition to other variants impacting this same amino acid (p.Arg487Trp and p.Arg487Gly) have been reported in individuals with allergic disease, however specific details were not provided (Supplementary Table 1, Frischmeyer-Guerrerio et al. 2013. PubMed ID: 23884466). In addition, other variants impacting the p.Arg487 amino acid have been reported in individuals with Loeys-Dietz syndrome type 1 (p.Arg487Trp, Loeys et al. 2006. PubMed ID: 16928994; p.Arg487Pro, Loeys et al. 2005. PubMed ID: 15731757). Functional studies have shown that this variant impacts TGFBR1 protein function (Goudie et al. 2011. PubMed ID: 21358634). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as pathogenic. - |
Loeys-Dietz syndrome;C4707243:Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 19, 2014 | The Arg487Gln variant (TGFBR1) has been reported in the literature in six indivi duals with clinical features of Loeys-Dietz syndrome, with de novo occurrence of the variant confirmed in two of the probands (Loeys 2006, Matyas 2006, Melenovs ky 2008, Yang 2012). In addition, functional analyses revealed that the mutant p rotein alters the normal function of the TGFBR1 protein (Barnett 2011, Goudie 20 11). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) based upon de novo occurrence in symptomatic ind ividuals and observed functional effect of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at