ClinVar Miner

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

dbSNP: 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, Mass General Brigham 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with Loeys -Dietz syndrome and was found to occur de novo in one of these individuals (Loey s 2005, Loeys 2006, LMM unpublished data).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 gm.partners.org/LMM).
GeneDx RCV000200178 SCV000250955 pathogenic not provided 2019-05-21 criteria provided, single submitter clinical testing Reported in ClinVar as pathogenic but additional evidence is not available (ClinVar Variant ID# 12511; Landrum et al., 2016); Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate variant has a dominant-negative effect on the TGFBR2 gene (Horbelt et al., 2010; Inamoto et al., 2010; Barnett et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22488992, 30406707, 15731757, 21267002, 21098638, 17470566, 18781618, 19996017, 20628007, 23103230, 16791849, 23884466, 27879313, 16928994, 27508510, 31536524, 32152251)
Invitae RCV000654809 SCV000776709 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2023-08-07 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt TGFBR2 function. ClinVar contains an entry for this variant (Variation ID: 12511). This missense change has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 15731757, 16928994, 19996017, 20956634, 22488992, 23103230, 25116393). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 528 of the TGFBR2 protein (p.Arg528His).
OMIM RCV000013335 SCV000033582 pathogenic Loeys-Dietz syndrome 2 2005-03-01 no assertion criteria provided literature only
OMIM RCV000013336 SCV000033583 pathogenic Colorectal cancer, hereditary nonpolyposis, type 6 2005-03-01 no assertion criteria provided literature only

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