ClinVar Miner

Submissions for variant NM_003238.5(TGFB2):c.905G>A (p.Arg302His) (rs1553303213)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000620397 SCV000739703 likely pathogenic Cardiovascular phenotype 2018-03-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Well-characterized mutation at same position,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence
GenomeConnect, ClinGen RCV000509486 SCV000607004 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000687648 SCV000815230 uncertain significance Holt-Oram syndrome 2018-05-23 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 302 of the TGFB2 protein (p.Arg302His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TGFB2-related disease. ClinVar contains an entry for this variant (Variation ID: 440982). This variant is also known as p.Arg330His on the literature. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg302Cys, also known as R330C) has been determined to be pathogenic (PMID: 25644172, 22772368). This suggests that the arginine residue is critical for TGFB2 protein function and that other missense substitutions at this position may also be pathogenic. 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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