ClinVar Miner

Submissions for variant NM_003239.4(TGFB3):c.412T>G (p.Ser138Ala) (rs201453600)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000618312 SCV000739713 uncertain significance Cardiovascular phenotype 2016-01-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
Center for Human Genetics, Inc RCV000660313 SCV000782353 uncertain significance Loeys-Dietz syndrome 5 2016-11-01 criteria provided, single submitter clinical testing
GeneDx RCV000489572 SCV000577539 uncertain significance not provided 2018-06-06 criteria provided, single submitter clinical testing The S138A variant of uncertain significance in the TGFB3 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In addition, this substitution occurs at a position that is conserved through mammals. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, the S138A variant is observed in 14/66688 alleles (0.02%) from individuals of European (Non-Finnish) background in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016).
Illumina Clinical Services Laboratory,Illumina RCV000279861 SCV000388859 uncertain significance Arrhythmogenic right ventricular cardiomyopathy 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000226558 SCV000287909 uncertain significance Loeys-Dietz syndrome 4 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces serine with alanine at codon 138 of the TGFB3 protein (p.Ser138Ala). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and alanine. This variant is present in population databases (rs201453600, ExAC 0.02%), 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 TGFB3-related disease. ClinVar contains an entry for this variant (Variation ID: 239520). 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 tolerated, 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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