ClinVar Miner

Submissions for variant NM_001101.5(ACTB):c.586C>T (p.Arg196Cys) (rs281875333)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000059720 SCV000617032 likely pathogenic not provided 2017-04-03 criteria provided, single submitter clinical testing The R196C variant has been published as a pathogenic variant in association with Baraitser-Winter syndrome and observed de novo (Di Donato et al., 2014; Rivière et al., 2012; Verloes et al., 2015). The R196C variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R196C 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. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Another missense variant in this residue (R196H) has been reported in the Human Gene Mutation Database in association with Baraitser-Winter syndrome (Stenson et al., 2014).
Invitae RCV000022440 SCV001214546 pathogenic Baraitser-Winter syndrome 1 2019-04-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 196 of the ACTB protein (p.Arg196Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with Baraitser-Winter syndrome (PMID: 25052316, 22366783, 23756437). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 29600). 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. 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. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000022440 SCV000043729 pathogenic Baraitser-Winter syndrome 1 2014-02-01 no assertion criteria provided literature only
UniProtKB/Swiss-Prot RCV000059720 SCV000091290 not provided not provided no assertion provided not provided
Department of Genetics,Robert DEBRE University Hospital RCV000022440 SCV000148643 pathogenic Baraitser-Winter syndrome 1 2014-04-15 no assertion criteria provided clinical testing
GeneReviews RCV000022440 SCV000257375 pathogenic Baraitser-Winter syndrome 1 2015-09-17 no assertion criteria provided literature only

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