ClinVar Miner

Submissions for variant NM_000138.4(FBN1):c.2861G>A (p.Arg954His) (rs112911555)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000181469 SCV000233771 uncertain significance not provided 2017-06-21 criteria provided, single submitter clinical testing The R954H variant has been published in at least one person with Marfan syndrome (Soylen et al., 2009). The R954H variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. A missense variant in the same residue (R954C) has been reported in the Human Gene Mutation Database in association with incomplete Marfan syndrome (Stenson et al., 2014), though the precise clinical significance of this variant has not yet been determined. Additionally, the R954H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. Lastly, R954H does not affect a cysteine residue within a calcium-binding EGF-like domain of the FBN1 gene. Cysteine substitutions in the calcium-binding EGF-like domains represent the majority of pathogenic missense changes associated with Marfan syndrome (Collod-Béroud et al., 2003).
Blueprint Genetics RCV000208533 SCV000263899 likely pathogenic Marfan syndrome 2015-10-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000253911 SCV000318124 uncertain significance Cardiovascular phenotype 2015-10-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Center for Medical Genetics Ghent,University of Ghent RCV000208533 SCV000786899 likely pathogenic Marfan syndrome 2017-11-07 no assertion criteria provided clinical testing

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