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

gnomAD frequency: 0.00003  dbSNP: rs387906696

Total submissions: 8

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).
Labcorp Genetics (formerly Invitae), Labcorp	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
All of Us Research Program, National Institutes of Health	RCV003996113	SCV004829440	uncertain significance	Loeys-Dietz syndrome	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces asparagine with serine at codon 45 of the TGFBR1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with thoracic aortic aneurysm and dissection, one sporadic and the other with family history of thoracic aortic aneurysm and dissection and sudden unexplained death (PMID: 29907982, 33824467). This variant has also been reported in two related individuals affected with multiple self-healing squamous epithelioma as well as in an unaffected family member (PMID: 21358634). This variant has been identified in 3/282384 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
OMIM	RCV000022802	SCV000044091	risk factor	Multiple self-healing squamous epithelioma	2011-02-27	no assertion criteria provided	literature only