ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.757A>G (p.Met253Val) (rs886038919)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000250999 SCV000319128 likely pathogenic Cardiovascular phenotype 2020-07-07 criteria provided, single submitter clinical testing The p.M253V variant (also known as c.757A>G) is located in coding exon 4 of the TGFBR1 gene in the protein kinase domain. This alteration results from an A to G substitution at nucleotide position 757. The methionine at codon 253 is replaced by valine, an amino acid with some highly similar properties, and is located in a protein kinase domain. This variant has been identified in an individual with Loeys-Dietz syndrome symptoms (Ambry internal data). Another alteration at the same codon, p.M253I (c.759G>A) has been reported in individuals with Marfan syndrome and Loeys-Dietz syndrome, with segregation of disease reported in at least one family (Singh KK et al. Hum. Mutat., 2006 Aug;27:770-7; Stheneur C et al. Hum. Mutat., 2008 Nov;29:E284-95; Söylen B et al. Clin. Genet., 2009 Mar;75:265-70; Beckmann E et al. Ann. Thorac. Surg., 2014 May;97:e125-7; Jondeau G et al. Circ Cardiovasc Genet, 2016 Dec;9:548-558). In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001042584 SCV001206274 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-08-26 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 253 of the TGFBR1 protein (p.Met253Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals with clinical features of TGFBR1-related conditions (Invitae, external communication). ClinVar contains an entry for this variant (Variation ID: 263773). 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: Possibly Damaging; Align-GVGD: Class C1). 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. This variant disrupts the p.Met253 amino acid residue in TGFBR1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16799921, 18781618, 31624717). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Clinical Molecular Genetics Laboratory,Johns Hopkins All Children's Hospital RCV000582499 SCV000692262 likely pathogenic Loeys-Dietz syndrome 2017-05-31 no assertion criteria provided clinical testing

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.