Submissions for variant NM_003242.6(TGFBR2):c.1680C>G (p.Asp560Glu)

dbSNP: rs376815143

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000154536	SCV000204208	uncertain significance	not specified	2011-11-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001186003	SCV001352328	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-03-21	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 560 of the TGFBR2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with TGFBR2-related disorders in the literature. This variant has not been identified 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.
GeneDx	RCV001843485	SCV002102636	uncertain significance	not provided	2022-03-02	criteria provided, single submitter	clinical testing	Reported as a variant of uncertain significance in an individual with a Marfan syndrome-like phenotype (Lerner-Ellis et al., 2014); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 24793577)
Ambry Genetics	RCV001186003	SCV002715266	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2021-03-02	criteria provided, single submitter	clinical testing	The c.1680C>G (p.D560E) alteration is located in exon 7 (coding exon 7) of the TGFBR2 gene. This alteration results from a C to G substitution at nucleotide position 1680, causing the aspartic acid (D) at amino acid position 560 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001186003	SCV004344521	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2023-05-28	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 560 of the TGFBR2 protein (p.Asp560Glu). 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. 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 TGFBR2 protein function. ClinVar contains an entry for this variant (Variation ID: 177885). This missense change has been observed in individual(s) with Marfan syndrome (PMID: 24793577). This variant is not present in population databases (gnomAD no frequency).
All of Us Research Program, National Institutes of Health	RCV003998251	SCV004841450	uncertain significance	Loeys-Dietz syndrome 2	2023-09-17	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glutamic acid at codon 585 of the TGFBR2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has not been identified 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.