Submissions for variant NM_003242.6(TGFBR2):c.902A>G (p.His301Arg)

dbSNP: rs863223857

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200455	SCV000250964	uncertain significance	not provided	2016-07-26	criteria provided, single submitter	clinical testing	The H301R variant in the TGFBR2 gene has been detected in three individuals reported to have Loeys- Dietz syndrome (Frischmeyer-Guerrerio et al., 2013); however, no segregation studies or clinical information was provided. The H301R variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Moreover, a missense variant in a nearby residue (L308P) has been reported in association with a TGFBR2-related disorder (Stenson et al., 2014). Nevertheless, the H301R variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Furthermore, to our knowledge, no studies have been performed to determine the functional effect of the H301R variant. Thus, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or benign.
Ambry Genetics	RCV000251947	SCV000319183	uncertain significance	Cardiovascular phenotype	2013-11-01	criteria provided, single submitter	clinical testing	The p.H301R variant (also known as c.902A>G), located in coding exon 4 of the TGFBR2 gene, results from an A to G substitution at nucleotide position 902. The histidine at codon 301 is replaced by arginine, an amino acid with highly similar properties, and is located in a serine/threonine protein kinase domain. This variant was detected in 3 individuals from a Loeys-Dietz syndrome cohort; however, clinical details were not provided (Frischmeyer-Guerrerio PA. Sci Transl Med. 2013 Jul;5(195):195ra94). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590283	SCV000698199	likely pathogenic	Loeys-Dietz syndrome	2019-02-28	criteria provided, single submitter	clinical testing	Variant summary: TGFBR2 c.902A>G (p.His301Arg) results in a non-conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This is supported by a study evaluating variants in TGFBR2 using genomics and structure based evaluations that classified this variant as "Pathogenic" (Zimmermann_2017). The variant was absent in 245738 control chromosomes. c.902A>G has been reported in the literature in 3 individuals affected with Loeys-Dietz Syndrome (Frischmeyer-Guerrerio 2013), and in 1 familial case tested in our laboratory, where the variant segregated with a strong family history of abdominal and aortic aneurysms/dissections. These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV003528156	SCV004293433	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection	2022-10-28	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt TGFBR2 function. ClinVar contains an entry for this variant (Variation ID: 213943). This missense change has been observed in individuals with clinical features of thoracic aortic aneurysm and dissection and/or Loeys-Dietz syndrome (PMID: 23884466; Invitae; external communication). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 301 of the TGFBR2 protein (p.His301Arg).