ClinVar Miner

Submissions for variant NM_003242.6(TGFBR2):c.1063G>C (p.Ala355Pro)

dbSNP: rs104893813
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Total submissions: 4
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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 RCV001193761 SCV001362855 likely pathogenic Loeys-Dietz syndrome 2019-06-24 criteria provided, single submitter clinical testing Variant summary: TGFBR2 c.1063G>C (p.Ala355Pro) 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. The variant was absent in 245344 control chromosomes (gnomAD and Loeys_2005). c.1063G>C has been reported in the literature in individuals affected with Loeys-Dietz Syndrome (Loeys_2005). These data indicate that the variant may be associated with disease. One study demonstrated intracellular accumulation of collagen type I in fibroblasts collected from the patient carrying this variant (Barnett_2011). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253567 SCV001429354 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 6 2019-12-10 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001851822 SCV002305432 likely pathogenic Familial thoracic aortic aneurysm and aortic dissection 2021-06-12 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 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. This variant has been observed in individual(s) with clinical features of TGFBR2-related conditions (PMID: 15731757, Invitae). ClinVar contains an entry for this variant (Variation ID: 12509). This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with proline at codon 355 of the TGFBR2 protein (p.Ala355Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline.
OMIM RCV000013333 SCV000033580 pathogenic Loeys-Dietz syndrome 2 2005-03-01 no assertion criteria provided literature only

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