ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1177T>G (p.Cys393Gly)

dbSNP: rs2125436754
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001986598 SCV002281480 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2024-01-02 criteria provided, single submitter clinical testing This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 393 of the TGFBR2 protein (p.Cys393Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Loeys-Dietz syndrome (PMID: 23884466, 27879313; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1493592). 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 with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Johns Hopkins Genomics, Johns Hopkins University RCV003485757 SCV004239047 likely pathogenic Loeys-Dietz syndrome 2 2024-01-17 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003485757 SCV004824311 uncertain significance Loeys-Dietz syndrome 2 2023-06-08 criteria provided, single submitter clinical testing This missense variant replaces cysteine with glycine at codon 393 of the TGFBR2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with Loeys-Dietz syndrome (PMID: 23884466) and in two individuals affected with thoracic aortic disease (PMID: 27879313). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this var, iant is classified as a Variant of Uncertain Significance.

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