ClinVar Miner

Submissions for variant NM_001101.5(ACTB):c.617G>A (p.Arg206Gln) (rs886039472)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000255779 SCV000322073 pathogenic not provided 2016-06-16 criteria provided, single submitter clinical testing The R206Q pathogenic variant in the ACTB gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R206Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Missense variants in nearby residues (A204G, V209M) have been reported in the Human Gene Mutation Database in association with Baraitser-Winter syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret R206Q as a pathogenic variant.
Ambry Genetics RCV000623638 SCV000742518 uncertain significance Inborn genetic diseases 2017-05-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: LIKELY POSITIVE: Relevant Alteration(s) Detected
Mendelics RCV000987816 SCV001137273 uncertain significance Baraitser-Winter syndrome 1 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000987816 SCV001393543 pathogenic Baraitser-Winter syndrome 1 2019-07-16 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 206 of the ACTB protein (p.Arg206Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in an individual affected with clinical features of Baraitser-Winter syndrome and in a fetus with cardiac malformations (Invitae, PMID: 29261186). ClinVar contains an entry for this variant (Variation ID: 265318). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant disrupts the p.Arg206 amino acid residue in ACTB. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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