ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1151A>G (p.Asn384Ser) (rs193922660)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000030542 SCV000053213 likely pathogenic Loeys-Dietz syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Likely pathogenic.
Invitae RCV000811071 SCV000951318 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-02-04 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 384 of the TGFBR2 protein (p.Asn384Ser). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with thoracic aortic aneurysm and dissection (PMID: 16799921, 16928994, Invitae). ClinVar contains an entry for this variant (Variation ID: 36860). 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. For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001000796 SCV001157856 likely pathogenic not specified 2018-10-02 criteria provided, single submitter clinical testing The TGFBR2 c.1151A>G; p.Asn384Ser variant (rs193922660) has been described in multiple individuals with features of Loeys-Dietz syndrome (Frederic 2009, Loeys 2006, Singh 2006). This variant contains an entry in ClinVar (Variation ID: 36860) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The asparagine at codon 384 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that this variant is deleterious. Moreover, multiple missense variants in neighboring codons also located in the serine-threonine kinase domain have been identified in cohorts of Loeys-Dietz syndrome patients (Stheneur 2008). Based on available information, this variant is considered likely pathogenic. REFERENCES Frederic MY et al. A new locus-specific database (LSDB) for mutations in the TGFBR2 gene: UMD-TGFBR2. Hum Mutat. 2008 Jan;29(1):33-8. Loeys BL et al. Aneurysm syndromes caused by mutations in the TGF-beta receptor. N Engl J Med. 2006 Aug 24;355(8):788-98. Singh KK et al. TGFBR1 and TGFBR2 mutations in patients with features of Marfan syndrome and Loeys-Dietz syndrome. Hum Mutat. 2006 Aug;27(8):770-7. Stheneur C et al. Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotype-phenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related disorders. Hum Mutat. 2008 Nov;29(11):E284-95.

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