ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.134A>G (p.Asn45Ser)

gnomAD frequency: 0.00003  dbSNP: rs387906696
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766900 SCV000250868 uncertain significance not provided 2022-02-25 criteria provided, single submitter clinical testing Identified in an individual with aortic dissection, multiple aortic and arterial aneurysms, hypermobility, and a significant family history, although segregation data was not available (Overwater et al., 2018); Observed in one Scottish family with multiple self-healing squamous epithelioma (MSSE); however, it was identified in two symptomatic relatives and one asymptomatic relative (Goudie D et al., 2011), and additional evidence is needed to establish the association between TGFBR1 variants and MSSE; Not observed at significant frequency in large population cohorts (gnomAD); 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: 25275298, 23358093, 28498993, 23358096, 24747516, 33824467, 29907982, 21358634)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000454530 SCV000540520 uncertain significance not specified 2016-12-16 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in a Scottish family with Multiple self-healing squamous epithelioma (MSSE - 2 affected and 1 unaffected relative). This variant is classified in ClinVar with 1 star as Pathogenic by GeneDx and a risk factor by OMIM. It has a Max MAF of 0.006% in ExAC (1 allele) and 0.003% in gnomAD (1 allele).
Invitae RCV000654793 SCV000776693 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2023-02-21 criteria provided, single submitter clinical testing 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 not expected to disrupt TGFBR1 protein function. ClinVar contains an entry for this variant (Variation ID: 29915). This missense change has been observed in individuals with multiple self-healing squamous epithelioma and/or thoracic aortic aneurysms and dissections (PMID: 21358634, 29907982, 33824467; Invitae). This variant is present in population databases (rs387906696, gnomAD 0.004%). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 45 of the TGFBR1 protein (p.Asn45Ser). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Vascular Biology, Beijing Anzhen Hospital RCV001374784 SCV001439501 uncertain significance Isolated thoracic aortic aneurysm 2018-09-01 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV000654793 SCV002043331 uncertain significance Familial thoracic aortic aneurysm and aortic dissection 2019-12-13 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002477006 SCV002800877 uncertain significance Loeys-Dietz syndrome 1; Multiple self-healing squamous epithelioma 2021-10-29 criteria provided, single submitter clinical testing
OMIM RCV000022802 SCV000044091 risk factor Multiple self-healing squamous epithelioma 2011-02-27 no assertion criteria provided literature only

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