ClinVar Miner

Submissions for variant NM_004612.4(TGFBR1):c.1141C>T (p.Pro381Ser) (rs760555508)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780772 SCV000918305 likely benign not specified 2017-09-20 criteria provided, single submitter clinical testing Variant summary: The TGFBR1 c.1141C>T (p.Pro381Ser) variant causes a missense change involving the alteration of a conserved nucleotide. 5/5 in silico tools predict a damaging outcome for this variant. The variant was found in the control population dataset of gnomAD in 14/245990 control chromosomes at a frequency of 0.0000569, which is approximately 30 times the estimated maximal expected allele frequency of a pathogenic TGFBR1 variant (0.0000019), suggesting this variant is likely a benign polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely benign.
Invitae RCV000654791 SCV000776691 uncertain significance Thoracic aortic aneurysm and aortic dissection 2017-11-07 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 381 of the TGFBR1 protein (p.Pro381Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs760555508, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with TGFBR1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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