Submissions for variant NM_004612.4(TGFBR1):c.733G>A (p.Glu245Lys) (rs1057524497)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436157	SCV000535729	likely pathogenic	not provided	2017-10-30	criteria provided, single submitter	clinical testing	The E245K variant in the TGFBR1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The E245K variant is not observed in large population cohorts (Lek et al., 2016). The E245K variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant at the same codon (E245G) has been reported in two unrelated individuals with multiple clinical features of TGFBR1-related disorders, supporting the functional importance of this region of the protein (Stheneur et al., 2008; Carmignac et al., 2012). We interpret E245K as a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America	RCV000436157	SCV000698486	uncertain significance	not provided	2016-02-19	criteria provided, single submitter	clinical testing	Variant summary: Variant affects a conserved nucleotide and results in a replacement of a medium size and acidic Glutamic acid (E) with a large size and basic Lysine (K). 4/5 in silico tools predict the variant to be damaging. It is absent from the large and broad cohorts of the ExAC project and to our knowledge, it was not reported in LDS or TAAD patients either. In vitro/vivo studies to assess the effect of the variant on the function of the protein were not reported at the time of scoring. Due to the lack of clinical data and functional studies, the variant was classified as a variant of uncertain significance until more information becomes available.
Invitae	RCV000804845	SCV000944778	uncertain significance	Thoracic aortic aneurysm and aortic dissection	2018-11-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid with lysine at codon 245 of the TGFBR1 protein (p.Glu245Lys). 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). This variant has not been reported in the literature in individuals with TGFBR1-related disease. ClinVar contains an entry for this variant (Variation ID: 392456). 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 and their clinical significance is uncertain. This variant disrupts the p.Glu245 amino acid residue in TGFBR1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 18781618, 23103230), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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.