ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.779C>T (p.Thr260Ile) (rs869025501)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000696020 SCV001335315 uncertain significance Rasopathy 2020-03-09 reviewed by expert panel curation The c.779C>T (p.Thr260Ile) variant in RAF1 was absent from large population databases (PM2; gnomad.broadinstitute.org). It occurs in the CR2 domain of the protein, which has been identified as a region important for protein function (PM1, 29493581). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID: 20679480). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been observed in multiple probands who lacked consistent RASopathy phenotypes; however, many probands presented with cardiomyopathy (PMID: 17603483; Blueprint Genetics internal data, SCV000264163.2; Invitae internal data, SCV000824563.1; Ambry internal data, SCV000740058.2; GeneDx internal data, SCV000582743.4). Although criteria suggest that this variant is likely pathogenic given its location and in vitro functional studies, the lack of clear clinical presentations of a RASopathy phenotype supports that this variant is of uncertain significance at this time. RASopathy-specific ACMG/AMP criteria applied: PS3, PM1, PM2, PP2.
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.
Ambry Genetics RCV000617372 SCV000740058 likely pathogenic Cardiovascular phenotype 2016-10-31 criteria provided, single submitter clinical testing The p.T260I variant (also known as c.779C>T), located in coding exon 6 of the RAF1 gene, results from a C to T substitution at nucleotide position 779. The threonine at codon 260 is replaced by isoleucine, an amino acid with similar properties. This alteration is located in the consensus recognition site for 14-3-3, which is a hotspot for Noonan syndrome (NS) mutations. Mutations in this region have been associated with a high prevalence of hypertrophic cardiomyopathy (HCM), and this variant has been previously reported in an HCM cohort (Pandit B et al. Nat. Genet. 2007;39:1007-12). Functional studies have demonstrated that this alteration leads to decreased phosphorylation of an invariant phosphorylated serine in the 14-3-3 recognition site, impaired 14-3-3 binding affinity, and increased RAF1 catalytic activity (Molzan M et al. Mol. Cell. Biol. 2010;30:4698-711). Furthermore, a likely pathogenic alteration affecting the same codon (p.T260R) has been reported in an individual with NS (Pandit B et al. Nat. Genet. 2007;39:1007-12). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000696020 SCV000824563 pathogenic Rasopathy 2020-09-17 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 observed in individual(s) with clinical features of Noonan syndrome (PMID: 17603483, Invitae). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 222774). Experimental studies have shown that this variant affects RAF1 protein function (PMID: 20679480). This variant disrupts the p.Thr260 amino acid residue in RAF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17603483, 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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