ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.605C>T (p.Ala202Val) (rs1564161322)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000798557 SCV000938178 uncertain significance Thoracic aortic aneurysm and aortic dissection 2018-11-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with valine at codon 202 of the TGFBR1 protein (p.Ala202Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of thoracic aortic aneurysm or aortic disease (PMID: 27146836, 27879313). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000786409 SCV000925227 uncertain significance not provided 2016-11-08 no assertion criteria provided provider interpretation The patient had genetic testing by the Collagen Diagnostics Laboratory. It looked for variants in 15 genes associated with aneurysms and dissections: ACTA2, COL3A1, FBN1, FBN2, MAT2A, MYH11, MYLK, MYH11, PRKG1, SKI, SLC2A10, SMAD3, TGFB3, TGFBR1, TGFBR2. Results reported on October 24, 2016 show that a variant was found: p.Ala202Val in the TGFBR1 gene. See report below. p.Ala202Val (c.605C>T) in the TGFBR1 gene The lab classifies this variant as a variant of unknown significance. Given insufficient case data, and lack of segregation data we consider this variant a variant of unknown significance, but is highly suspicious. At this time we recommend further family studies to determine if this variant segregates with disease in the family. Currently we do feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). The variant has been seen in at least four unrelated cases of Loeys-Dietz syndrome as detailed below (not including this patient's family). There is no segregation data. In silico analysis with PolyPhen-2 predicts the variant to be probably damaging (HumVar = 1.00). The alanine at codon 202 is conserved across all 99 species, as are neighboring amino acids. This substituted amino acid is located between the glycine-serine-rich domain (GS domain that contains sites of activating phosphorylation) and the kinase domain (the catalytic domain ) of the type I TGFb receptor. At this time function of this junction region is not well characterized. Within this region, substitution at position 200 (p.Thr200Ile) was previously reported in a young child with Loeys-Dietz syndrome (Loeys et al, 2005). CDL has previously seen substitutions at positions 199 (p.Arg199Lys), 204 (p.Thr204Ile) and 205 (p.Ile205Thr) in individuals tested due to aortic aneurysms, however we have not been able to establish whether those variants are pathogenic. None of these nearby variants have been previously identified in the exac or gnomad browsers (indicating that they're sufficiently rare). There are three individuals with variation at position 202 listed in the Genome Aggregation Consortium Dataset (gnomAD;, which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The average coverage at that site in gnomAD is unavailable as of 10/31/2016.

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.