ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.779C>T (p.Thr260Ile) (rs869025501)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000617372 SCV000740058 likely pathogenic Cardiovascular phenotype 2016-10-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,Deficient protein function in appropriate functional assay(s),Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Blueprint Genetics, RCV000208050 SCV000264163 likely pathogenic Primary familial hypertrophic cardiomyopathy 2015-02-03 criteria provided, single submitter clinical testing
GeneDx RCV000494156 SCV000582743 likely pathogenic not provided 2017-05-05 criteria provided, single submitter clinical testing The T260I variant has been published in a patient diagnosed with hypertrophic cardiomyopathy (HCM) (Pandit et al., 2007) with limited evidence. The T260I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The T260I 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. Missense variants in the same (T260R) and in nearby residues (R256S, S257L, S259P/T/F, P261S/A/T/R/L, N262K/K) have been reported in the Human Gene Mutation Database in association with Noonan syndrome (Stenson et al., 2014), supporting the functional importance of this region of the protein. In summary, this variant is likely pathogenic.
Invitae RCV000696020 SCV000824563 uncertain significance Rasopathy 2018-06-20 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 260 of the RAF1 protein (p.Thr260Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with hypertrophic cardiomyopathy (PMID: 17603483). ClinVar contains an entry for this variant (Variation ID: 222774). Experimental studies have shown that this missense change alters protein function in vitro (PMID: 20679480). A different missense substitution at this codon (p.Thr260Arg) has been reported in an individual affected with Noonan syndrome (PMID: 17603483). 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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