ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.679G>A (p.Glu227Lys) (rs1060502042)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000471274 SCV000548335 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-07-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 227 of the TGFBR1 protein (p.Glu227Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TGFBR1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786408 SCV000925226 likely pathogenic not provided 2016-07-27 no assertion criteria provided provider interpretation p.Glu227Lys (c.679G>A) in the TGFBR1 gene (NM_004612.2) The lab classifies this variant as a variant of unknown significance. Given the patient's phenotype is consistent with Loeys-Dietz syndrome and there is lack of variation at this position in the general population and through evolution we consider this variant likely disease causing. This variant was not inherited from the patient's father and was likely inherited by the patient's mother who passed from an aortic dissection at 4.5 cm (at the AoSV) which indicates that she likely had Loeys-Dietz syndrome given her relatively small aortic diameter at the time of dissection. The variant is novel in this family. One of the patient's sisters who has hypermobility and a long uvula also tested positive for this variant. Cardiac evaluation is pending. In silico analysis with PolyPhen-2 predicts the variant to be pathogenic (HumVar: 0.998) and mutation taster agrees (0.999). The glutamic acid at codon 227 is conserved across species, as are neighboring amino acids. This variant is located in the catalytic kinase domain of the extracellular protein component and likely inhibits binding through the catalytic kinase domain. Other variants in this domain have been shown to be pathogenic. There is no variation at codon 227 listed in the Genome Aggregation database (, which currently includes variant calls on ~140,000 individuals of European, African, Latino and Asian descent (as of Jan 31, 2017) indicating that variation at this position is extremely rare. There is no variation listed in the gnomad database between codons 223 and 233 indicating that this area of the protein is not tolerant of missense variation and likely disrupts protein function.

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