ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1583G>A (p.Arg528His) (rs104893815)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000211858 SCV000203966 pathogenic Loeys-Dietz syndrome 2014-08-29 criteria provided, single submitter clinical testing The Arg528His variant in TGFBR2 has been identified in >8 individuals with Loeys -Dietz syndrome and was found to occur de novo in one of these individuals (Loey s 2005, Loeys 2006, LMM unpublished data). It was absent from large population s tudies. In vitro and in vivo functional studies provide evidence that the Arg528 His variant may impact protein function. Computational prediction tools and cons ervation analysis suggest that the Arg528His variant may impact the protein, tho ugh this information is not predictive enough to determine pathogenicity. In sum mary, this variant meets our criteria to be classified as pathogenic (http://pcp
GeneDx RCV000200178 SCV000250955 pathogenic not provided 2017-02-08 criteria provided, single submitter clinical testing The R528H mutation in the TGFBR2 gene has been reported previously in one individuals with Loeys-Dietz syndrome and in one individual with Marfanoid features and craniosynostosis (Loeys B et al., 2005; Carmignac V et al., 2012). Moreover, functional studies have show that R528H has a dominant-negative impact on the normal function of the TGFBR2 gene(Horbelt D et al., 2010; Barnett C et al., 2011). R528H results in a conservative amino acid substitution at a position that is well-conserved across species. Mutations in this residue (R528C, R528S) and in nearby residues (A527T, A527V, L529F, T530I) have been reported in association with Loeys-Dietz syndrome, further supporting the functional importance of this residue and region of the protein. Furthermore, the R528H mutation 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.In summary, R528H in the TGFBR2 gene is interpreted as a disease-causing mutation. This variant was found in TGFBR2
Invitae RCV000654809 SCV000776709 pathogenic Thoracic aortic aneurysm and aortic dissection 2018-02-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 528 of the TGFBR2 protein (p.Arg528His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Shprintzen-Goldberg Syndrome (PMID: 23103230), Loeys–Dietz Syndrome (PMID: 16928994, 19996017, 22488992, 25116393, 20956634), and in an individual with  cardiovascular, craniofacial, neurocognitive and skeletal development defects where it was reported to be de novo (PMID: 15731757). ClinVar contains an entry for this variant (Variation ID: 12511). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000013335 SCV000033582 pathogenic Loeys-Dietz syndrome 2 2005-03-01 no assertion criteria provided literature only
OMIM RCV000013336 SCV000033583 pathogenic Hereditary nonpolyposis colorectal cancer type 6 2005-03-01 no assertion criteria provided literature only

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