ClinGen Dosage Sensitivity Curation Page

RAF1

  • Curation Status: Complete

Location Information

Select assembly: (NC_000003.11) (NC_000003.12)
  • Haploinsufficiency score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Haploinsufficiency phenotype comments:

RAF1 encodes a serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade and functions in cell proliferation, differentiation, apoptosis, survival and oncogenic transformation. Germline mutations (through gain-of-function mechanism) have been implicated in Noonan syndrome, LEOPARD syndrome, and non-syndromic dilated cardiomyopathy. There are currently no reported patients with focal deletion or proven loss-of-function variants involving RAF1; therefore, the haploinsufficiency score is 0. Additional relevant literature is summarized below: PMID 24782337: Sana et al. (2014) reported a 2?month?old male who was originally diagnosed with biventricular hypertrophy, mild dysmorphic features (low?set posteriorly rotated ears, ocular hypertelorism, and prognathism) and without a family history of cardiovascular diseases. No caf?au?lait spots or lentigines were observed. Bilateral cryptorchidism was also present. Neurobehavioral assessment was normal for his age. Exome sequencing detected a de novo heterozygous three nucleotide deletion (NM_0022880.3: c.785_787del) in RAF1 that resulted in a deletion of two amino acids and an insertion of one amino acid (p.Asn262_Val263delinsIle), confirmed by Sanger. Known RAF1 mutations are clustered in the conserved region domain, which carries a regulatory site for inhibition by 14-3-3 proteins proximal to the serine at position 259. Structural analysis of RAF1 revealed that this variant fell in the binding site for 14-3-3 proteins. In particular, a docking interaction study suggested that this insertion/deletion impairs binding of RAF1 to 14-3-3 proteins, resulting in constitutive activation of Ras signaling, consistent with a gain-of-function mechanism of pathogenicity.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

RAF1 encodes a serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade and functions in cell proliferation, differentiation, apoptosis, survival and oncogenic transformation. Germline mutations (through gain-of-function mechanism) have been implicated in Noonan syndrome, LEOPARD syndrome, and non-syndromic dilated cardiomyopathy. Patients reported with non-focal duplications involving RAF1 lack a consistent clinical phenotype and a single report included inheritance of this duplication from a normal parent (summarized below). In addition, duplication in the region of 3p25.2 containing the RAF1 gene has been observed in multiple individuals in studies of natural genomic variation. There are currently no reported patients with focal duplication involving RAF1; therefore, the triplosensitivity score is 0. Additional relevant literature is summarized below: PMID 22786616: Luo et al. (2012) described a 15?year?old male with Noonan syndrome phenotype (short stature, heart defects, low posterior hairline, facial malformations, and malformed left ear with sensorineural hearing loss, widely spaced nipples, and unilateral upper limb anomaly). At age 13 the patient had surgical treatment of cardiac defects which included tetralogy of Fallot, secundum atrial septal defect and persistent left superior vena cava. This patient was initially diagnosed with Holt-Oram syndrome due to his combined cardiac anomalies and upper limb malformations (absence of thumbs, radial carpals, and radiuses). Sequence analysis did not identify mutations in genes associated with Holt?Oram syndrome. High resolution SNP array detected a de novo 0.25?Mb microduplication at 3p25.2 encompassing the genes RAF1 and MKRN2 and partially overlapping two additional genes (TSEN2 and TMEM40). The authors suggest duplication of RAF1 could cause Noonan syndrome. PMID 25974318: Lissewski et al. (2015) described a male patient (patient 2) with significant expressive language delay. The patient was the fourth child of non-consanguineous Caucasian parents and was delivered at 37 weeks with no major congenital anomalies. At presentation (3.5 years) his growth parameters were normal, however exhibited dysmorphic features which included fleshy, slightly low-set and posteriorly rotated ears and had mild pectus carinatum. SNP microarray identified a 0.16 Mb duplication on 3p25.2 encompassing RAF1 and a few other genes (MKRN2 and partial copies of TSEN2 and TMEM40). The duplication was paternally inherited; the father had no dysmorphic features or intellectual disability (had completed secondary education). The authors conclude that there is a lack of a specific phenotype justifying a clinical rasopathy diagnosis in the patients reported so far in the literature, including this patient. They further argued that gene duplication and resulting modest increase in gene expression does not result in similar phenotypic findings as missense mutations associated with a gain-of-function of the abnormal protein product. In addition there is lack of functional studies confirming increased expression levels of the respective gene products associated with genomic duplications containing RAS pathway genes. (See also PMID 26137925: Gripp, Commentary)