ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.214A>T (p.Ile72Leu) (rs111513627)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154851 SCV000204533 uncertain significance not specified 2013-06-24 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The Ile72Leu varian t in TGFBR1 has not been reported in individuals with clinical features of Loeys -Dietz syndrome, but has been identified in 0.1% (1/1126) of chromosomes from a clinically and racially unspecified population, and in 0.03% (3/8600) of Europea n American chromosomes by the NHLBI Exome Sequencing Project (; dbSNP rs111513627). While this frequency suggests that this var iant is more likely benign, it is too low to confidently rule out a disease caus ing role. Computational analyses (biochemical amino acid properties, conservatio n, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. In summary, additional information is needed to fully assess the clinical significance of the Ile72Leu variant.
GeneDx RCV000154851 SCV000250904 uncertain significance not specified 2016-12-06 criteria provided, single submitter clinical testing The I72L variant of uncertain significance in the TGFBR1 gene has been reported both a sporadic case and a familial case of abdominal aneurysm; however, this variant did not appear to be segregating with disease in the familial case (van de Luijtgaarden et al., 2015). This variant has also been identified, both independently and in conjunction with additional cardiogenetic variants, in several individuals referred for TAAD-related testing at GeneDx. However, thus far, segregation data is limited or absent for these individuals due to the lack of clinical information provided and/or insufficient participation by informative family members. The I72L variant was not observed with any significant frequency in both the Exome Aggregation Consortium and in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. Nevertheless, the I72L variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Additionally, this substitution occurs at a position where amino acids with similar properties to Isoleucine are tolerated across species. Furthermore, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign. This result cannot be interpreted for diagnosis or used for family member screening at this time.
Invitae RCV000551891 SCV000658848 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-07-11 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 72 of the TGFBR1 protein (p.Ile72Leu). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs111513627, ExAC 0.03%). This variant has been reported in two individuals affected with abdominal aortic aneurysm (PMID: 26017485) and in an individual with an undetermined connective tissue disorder (PMID: 27011056). ClinVar contains an entry for this variant (Variation ID: 178136). 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 tolerated, but these predictions have not been confirmed by published functional studies. 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.
Blueprint Genetics RCV000788208 SCV000927246 uncertain significance not provided 2017-05-03 criteria provided, single submitter clinical testing

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