Submissions for variant NM_003242.6(TGFBR2):c.1483C>T (p.Arg495Ter)

dbSNP: rs104893819

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000195964	SCV000250967	pathogenic	not provided	2022-06-01	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies suggest a damaging effect by causing intracellular accumulation of collagen type I in patient-derived cultured fibroblasts (Barnett et al., 2011); Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is not a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 16928994, 18084123, 22113417, 17652900, 33059708, 34150014, 21267002, 26582918, 33084842)
Ambry Genetics	RCV000253575	SCV000319544	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2023-05-15	criteria provided, single submitter	clinical testing	The p.R495* pathogenic mutation (also known as c.1483C>T), located in coding exon 6 of the TGFBR2 gene, results from a C to T substitution at nucleotide position 1483. This changes the amino acid from an arginine to a stop codon within coding exon 6. This alteration occurs at the 3' terminus of theTGFBR2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 12.8% of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in several individuals and families with a diagnosis of Loeys-Dietz syndrome (Loeys et al. N Engl J Med. 2006;355(8):788-98; Togashi et al. Intern Med. 2007;46(24):1995-2000; Yang et al. J Hum Genet. 2012;57:52-6). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae	RCV000253575	SCV000658821	pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg495*) in the TGFBR2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 73 amino acid(s) of the TGFBR2 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with Loeys-Dietz syndrome (PMID: 16928994, 17652900, 18084123, 22113417). ClinVar contains an entry for this variant (Variation ID: 12519). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000763512	SCV000894313	pathogenic	Loeys-Dietz syndrome 2; Malignant tumor of esophagus; Colorectal cancer, hereditary nonpolyposis, type 6	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000157519	SCV000918308	pathogenic	Loeys-Dietz syndrome	2018-01-30	criteria provided, single submitter	clinical testing	Variant summary: TGFBR2 c.1483C>T (p.Arg495X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 245910 control chromosomes. The c.1483C>T variant has been reported in the literature in multiple individuals affected with Loeys-Dietz Syndrome, including segregation with disease in a family (Togashi_2007). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, where an increase in intracellular collagen was observed in patient fibroblasts (Barnett_2011). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, each of which classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000195964	SCV005198780	pathogenic	not provided	2022-10-31	criteria provided, single submitter	clinical testing
OMIM	RCV000013344	SCV000033591	pathogenic	Loeys-Dietz syndrome 2	2006-08-24	no assertion criteria provided	literature only
Blueprint Genetics	RCV000157519	SCV000207264	likely pathogenic	Loeys-Dietz syndrome	2014-07-21	no assertion criteria provided	clinical testing