ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.700T>C (p.Phe234Leu) (rs1060502046)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000473430 SCV000548347 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2020-10-06 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with leucine at codon 234 of the TGFBR1 protein (p.Phe234Leu). The phenylalanine residue is highly conserved and there is a small physicochemical difference between phenylalanine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with TGFBR1-related disease (PMID: 16928994, 26848186; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 408572). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). For these reasons, this variant has been classified as Pathogenic. 5
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001174650 SCV001337863 likely pathogenic Familial aortopathy 2020-01-30 criteria provided, single submitter clinical testing Variant summary: TGFBR1 c.700T>C (p.Phe234Leu) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) 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 251102 control chromosomes (gnomAD). p.Phe234Leu has been reported in the literature in individuals and families affected with Aortopathy/Loeys-Dietz Syndrome (e.g. Frischmeyer-Guerrerio_2013, Jondeau_2016, Loeys_2006, Teixido-Tura_2016, Universal Mutation Database). 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. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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