ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.1532C>T (p.Thr511Ile) (rs80338799)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000523483 SCV000616380 pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.1472C>T (p.Thr491Ile) variant in RAF1 has been reported in the literature in at least one individual with clinical features of a RASopathy (PS4 not met; PMID 17603483). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). 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 missense variants are common (PP2; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Thr491Ile variant may impact the protein (PP3). In vitro functional studies provide some evidence that the p.Thr491Ile variant may impact protein function (PS3; 20679480). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000037676 SCV000061338 pathogenic Noonan syndrome 2013-05-28 criteria provided, single submitter clinical testing The Thr491Ile has been identified in our laboratory in two probands with clinica l features of Noonan syndrome. In addition, this variant was not identified in t he parents of one proband in our laboratory, and therefore occurred de novo. Thi s variant has also been reported in the literature in one individual with clinic al features of Noonan syndrome and was not identified in 210 control individuals (Pandit 2007). Computational analyses (biochemical amino acid properties, conse rvation, AlignGVGD, and SIFT) suggest that the Thr491Ile variant may impact the protein. In summary, this variant meets our criteria to be classified as pathoge nic based on its de novo occurrence (http://pcpgm.partners.org/LMM).
GeneDx RCV000159086 SCV000209029 pathogenic not provided 2016-12-30 criteria provided, single submitter clinical testing The T491I missense variant in the RAF1 gene has been reported previously in association with Noonan syndrome (Pandit et al., 2007). The T491I variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). T491I occurs in the activation segment of the CR3 (conserved region 3) domain of the resulting protein. In vitro functional studies demonstrated that that presence of the T491I variant results in impaired MEK kinase expression and results in constitutive ERK activation (Pandit et al., 2007). Another missense variant at the same location (T491R) has also been reported in association with Noonan syndrome, indicating the functional importance of this residue. About 80% of individuals with a RAF1 variant develop hypertrophic cardiomyopathy (HCM). However, at least one patient with the T491I variant has been reported without HCM (Pandit et al., 2007).
Ambry Genetics RCV000621393 SCV000739974 likely pathogenic Cardiovascular phenotype 2016-07-06 criteria provided, single submitter clinical testing The p.T491I variant (also known as c.1472C>T), located in coding exon 13 of the RAF1 gene, results from a C to T substitution at nucleotide position 1472. The threonine at codon 491 is replaced by isoleucine, an amino acid with similar properties. This alteration has been reported in the literature in an individual with Noonan syndrome (Pandit B et al. Nat. Genet. 2007 Aug; 39(8):1007-12). Phosphorylation of the threonine at codon 491 has been shown to be important for the regulation of RAF1 activity, and the p.T491I variant has been shown to alter RAF1 function (Pandit B et al. Nat. Genet. 2007 Aug; 39(8):1007-12; Wu X et al. Mol. Cell. Biol. 2012 Oct; 32(19):3872-90). This variant was previously reported in the SNPDatabase as rs80338799. This variant was not reported in population-based cohorts in the following databases: NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneReviews RCV000020507 SCV000040958 pathologic Noonan syndrome with multiple lentigines 2010-11-16 no assertion criteria provided curation Converted during submission to Pathogenic.
Database of Curated Mutations (DoCM) RCV000037676 SCV000510557 likely pathogenic Noonan syndrome 2016-05-13 no assertion criteria provided literature only

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