ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.1721A>G (p.Tyr574Cys) (rs370242565)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000154479 SCV000204148 uncertain significance not specified 2016-07-01 criteria provided, single submitter clinical testing Variant classified as Uncertain Significance - Favor Benign. The p.Tyr574Cys var iant in RAF1 has been identified by our laboratory in 3 individuals with clinica l features of Noonan syndrome and in two of these cases it was inherited from a parent. The first individual inherited it from an unaffected parent. The second inherited it from a mildly affected parent; however, both the proband and mildly affected parent carried an additional likely pathogenic variant in PTPN11 sugge sting that the p.Tyr574Cys variant may not be the cause of their phenotype (LMM Data). This variant has been identified in 20/66732 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs3702 42565). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the cl inical significance of the p.Tyr574Cys variant is uncertain, these data suggest that it is more likely to be benign.
GeneDx RCV000154479 SCV000209030 uncertain significance not specified 2015-08-18 criteria provided, single submitter clinical testing p.Tyr574Cys (TAT>TGT): c.1721 A>G in exon 16 of the RAF1 gene (NM_002880.3). Mutations in the RAF1 gene are associated with Noonan spectrum disorders, including Noonan syndrome and LEOPARD syndrome. Germline RAF1 mutations occur in as many as 17% of patients with Noonan syndrome (Allanson J et al., 2011). A variant of unknown significance has been identified in the RAF1 gene. The Y574C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The Y574C variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The Y574C 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 when present across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, no missense mutations in nearby residues have been in association with disease, suggesting this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in CARDIOMYOPATHY panel(s).
Illumina Clinical Services Laboratory,Illumina RCV000407178 SCV000440621 uncertain significance Noonan syndrome with multiple lentigines 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000309941 SCV000440622 uncertain significance Noonan syndrome 2016-06-14 criteria provided, single submitter clinical testing
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000623835 SCV000740651 uncertain significance Primary familial hypertrophic cardiomyopathy 2016-08-08 criteria provided, single submitter clinical testing
Invitae RCV000692399 SCV000820220 uncertain significance Rasopathy 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 574 of the RAF1 protein (p.Tyr574Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs370242565, ExAC 0.03%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with RAF1-related disease. ClinVar contains an entry for this variant (Variation ID: 177842). 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 tolerated, 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. 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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