ClinVar Miner

Submissions for variant NM_002880.4(RAF1):c.776C>A (p.Ser259Tyr)

dbSNP: rs397516827
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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 RCV001250389 SCV001424751 pathogenic RASopathy 2020-05-18 reviewed by expert panel curation The c.776C>A (p.Ser259Tyr) variant in RAF1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 3 probands with clinical features of Noonan syndrome (PS4_Moderate; PMIDs: 31030682, 26918529, GeneDx internal data). In one proband, the variant occurred de novo with parentage confirmation (PS2; PMID: 31030682). The c.776C>A (p.Ser259Tyr) variant occurs in the CR2 activation domain of RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). A different pathogenic missense variant has been previously identified at this codon of RAF1 supporting this residue is critical to the function of the protein (PM5 not applied; ClinVar 40601). The variant is located in RAF1, 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). 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): PM2, PS4_Moderate, PS2, PM1, PP2.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000037702 SCV000061364 uncertain significance not specified 2016-02-11 criteria provided, single submitter clinical testing proposed classification - variant undergoing re-assessment, contact laboratory
Mendelics RCV000987117 SCV001136322 pathogenic LEOPARD syndrome 2 2019-05-28 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV001843945 SCV002103206 pathogenic not provided 2021-04-21 criteria provided, single submitter clinical testing PS2, PS4_moderate, PM1, PM2, PP2
Institute of Immunology and Genetics Kaiserslautern RCV004771458 SCV005382199 pathogenic Noonan syndrome 5 2022-04-27 criteria provided, single submitter clinical testing ACMG Criteria: PS2, PM1, PM2_P, PM5, PP3, PP5; Variant was found heterozygously in de novo-status by prenatal trio exome sequence analysis.
Service de Génétique Moléculaire, Hôpital Robert Debré RCV001261032 SCV001438433 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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