ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.1459C>T (p.Arg487Trp) (rs111426349)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617146 SCV000319363 pathogenic Cardiovascular phenotype 2018-04-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Strong segregation with disease (lod >3 = >10 meioses)
Blueprint Genetics RCV000200764 SCV000928187 pathogenic not provided 2019-01-22 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763611 SCV000894459 pathogenic Loeys-Dietz syndrome 1; Multiple self healing squamous epithelioma 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000200764 SCV000250898 pathogenic not provided 2018-11-02 criteria provided, single submitter clinical testing The R487W pathogenic variant in the TGFBR1 gene has been previously reported in association withLoeys-Dietz syndrome, isolated TAAD or aortic disease, and possible MFS (Loeys et al., 2006;Tran-Fadulu et al., 2009; Dong et al., 2014; Luo et al., 2016; Teixidó-Tura et al., 2016; Yang et al.,2016). This variant has been observed to segregate with disease in multiple affected relatives from atleast two unrelated families (Tran-Fadulu et al., 2009; Teixidó-Tura et al., 2016). The R487W pathogenic variant is notobserved in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015;Exome Variant Server). R487W results in a non-conservative amino acid substitution which is likely toimpact secondary protein structure as these residues differ in polarity, charge, size and/or otherproperties. This substitution occurs at a position that is conserved across species, and in silico analysispredicts this variant is probably damaging to the protein structure/function. Furthermore, anotherlikely pathogenic missense variant affecting the same residue (R487Q) has been reported multipletimes in association with TAAD and LDS (Loeys et al., 2006; Mátyás et al., 2006; Yang et al., 2012;Ting et al., 2014).
Invitae RCV000251089 SCV000548339 pathogenic Thoracic aortic aneurysm and aortic dissection 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 487 of the TGFBR1 protein (p.Arg487Trp). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is not present in population databases (rs111426349, ExAC no frequency). This variant has been reported to segregate with thoracic aortic aneurysm and dissections in two large families (PMID: 19542084, 25110237). It has also been reported in individuals affected with Loeys-Dietz syndrome (PMID: 23884466) and aortopathy (PMID: 27611364, 24793577). ClinVar contains an entry for this variant (Variation ID: 12526). Variants that disrupt the p.Arg487 amino acid residue in TGFBR1 have been observed in affected individuals (PMID: 23884466). This suggests that it is a clinically significant residue, and that other variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000211856 SCV000200566 pathogenic Loeys-Dietz syndrome; Thoracic aortic aneurysm and aortic dissection 2014-08-21 criteria provided, single submitter clinical testing The Arg487Trp variant in TGFBR1 has been reported in 4 individuals with clinical features of Loeys-Dietz syndrome (Loeys 2006, Frischmeyer-Guerrerio 2013, LMM u npublished). Additionally, the Arg487Trp variant was reported in 3 individuals w ith familial thoracic aortic aneurysm and dissection (TAAD) and segregated with disease in 13 affected relatives with TAAD from two of these families (Tran-Fadu lu 2009, Aragon-Martin 2013, Dong 2014). This variant was absent from large popu lation studies. Computational prediction tools and conservation analysis suggest that the Arg487Trp variant may impact the protein, though this information is n ot predictive enough to determine pathogenicity. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM).
OMIM RCV000013352 SCV000033599 pathogenic Loeys-Dietz syndrome 1 2009-09-01 no assertion criteria provided literature only

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