ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.1082G>C (p.Gly361Ala) (rs397516813)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000473341 SCV000616425 pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.1082G>C (p.Gly361Ala) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; GeneDx, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 506381 ClinVar SCV000209024.9). The p.Gly361Ala variant has been identified in at least 4 independent occurrences in patients with a RASopathy (PS4_Moderate; GeneDx, Partners LMM, Institute of Human Genetics, Otto von Guericke University Magdeburg internal data; GTR ID's: 26957, 21766, 506381; SCV000209024.9, SCV000061333.5). 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.Gly361Ala variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM6_Strong, PS4_Moderate, PM2, PP2, PP3.
GeneDx RCV000159081 SCV000209024 pathogenic not provided 2012-11-26 criteria provided, single submitter clinical testing The G361A missense variant was identified in the RAF1 gene. It has not been published as a pathogenic variant, nor has it been reported as a benign polymorphism to our knowledge. G361A is considered to be a conserved amino acid substitution with a small, nonpolar residue (Gly) being replaced by another small, nonpolar residue (Ala). However, Glycine is an invariant residue at this position in the encoded protein and in related proteins across multiple species. Multiple in silico models predict that any substitution for a Glycine at this position is probably detrimental. Additionally, the NHLBI ESP Exome Variant Server reports G361A was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a benign variant in these populations. Therefore, G361A is considered to be a pathogenic variant.
Invitae RCV000473341 SCV000552086 pathogenic Rasopathy 2016-11-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 361 of the RAF1 protein (p.Gly361Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a RAF1-related disease. ClinVar contains an entry for this variant (Variation ID: 40613). Family studies have indicated that this variant was not present in the parents of an individual with a RAF1-related condition, which suggests that it was de novo in that affected individual (Invitae). Experimental studies have shown that this missense change causes resistance to RAF inhibitors, reduces kinase activity and inhibits binding (PMID: 14701845, 23737487). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037671 SCV000061333 likely pathogenic Noonan syndrome 2016-02-17 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory

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