ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.913C>T (p.Leu305Phe)

dbSNP: rs1553630171
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519818 SCV000618263 likely pathogenic not provided 2022-08-23 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29339704)
Fulgent Genetics, Fulgent Genetics RCV000765721 SCV000897088 uncertain significance Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Colorectal cancer, hereditary nonpolyposis, type 6 2018-10-31 criteria provided, single submitter clinical testing
Invitae RCV001857962 SCV002170246 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2021-11-13 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Leu305 amino acid residue in TGFBR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 TGFBR2 protein function. ClinVar contains an entry for this variant (Variation ID: 449834). This missense change has been observed in individual(s) with Loeys-Dietz syndrome (PMID: 29339704). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 305 of the TGFBR2 protein (p.Leu305Phe).
Ambry Genetics RCV001857962 SCV002684798 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2021-04-13 criteria provided, single submitter clinical testing The p.L305F pathogenic mutation (also known as c.913C>T), located in coding exon 4 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 913. The leucine at codon 305 is replaced by phenylalanine, an amino acid with highly similar properties. This variant has been detected in two de novo cases with findings consistent with Loeys-Dietz syndrome (Ambry internal data; Kasar T et al. Anatol J Cardiol, 2018 Jan;19:74-77). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability and ligand binding (Tebben AJ et al. Acta Crystallogr D Struct Biol, 2016 05;72:658-74). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.