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

dbSNP: rs1057524497

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000436157	SCV000535729	likely pathogenic	not provided	2020-01-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000804845	SCV000944778	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2021-04-02	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. 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. 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 expected to disrupt TGFBR1 protein function. This variant has been observed in individual(s) with clinical features of TGFBR1-related conditions (External communication). ClinVar contains an entry for this variant (Variation ID: 392456). This variant is not present in population databases (ExAC no frequency). 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.