ClinVar Miner

Submissions for variant NM_002880.3(RAF1):c.788T>G (p.Val263Gly) (rs397516830)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Blueprint Genetics RCV000037708 SCV000207170 pathogenic Noonan syndrome 2014-07-07 no assertion criteria provided clinical testing
ClinGen RASopathy Variant Curation Expert Panel RCV000523845 SCV000616423 likely pathogenic Rasopathy 2017-04-03 reviewed by expert panel curation The c.788T>G (p.Val263Gly) variant in RAF1 has been reported in the literature as an unconfirmed de novo occurrence in a patient with clinical features of a RASopathy (PM6; GeneDx internal data; GTR ID: 26957; ClinVar SCV000061370.9). The p.Val263Gly variant has been identified in 6 other independent occurrences in patients with a RASopathy (PS4 not met; Partners LMM, Blueprint genetics, Institute of Human Genetics, Otto von Guericke University Magdeburg, APHP-Robert Debré Hospital internal data; GTR ID's: 21766, 500188, 506381, 28338; ClinVar SCV000209021.9, SCV000207170.1). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). A different pathogenic missense variant has been previously identified at this codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 496189, 40608). 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). 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.Val263Gly 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, PM5, PM2, PM1, PP3, PP2.
GeneDx RCV000159078 SCV000209021 pathogenic not provided 2012-03-18 criteria provided, single submitter clinical testing The V263G missense mutation has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. This mutation has been seen before at GeneDx and another missense mutation at this codon (V263A) was previously reported in a patient diagnosed with Noonan syndrome and hypertrophic cardiomyopathy (Razzaque et al., 2007). Furthermore, this mutation is located in a highly conserved portion of the RAF1 gene, where many other gain-of function mutations (P261A, P261S and P261L) have also been reported in association with Noonan syndrome (Pandit et al., 2007 and Razzaque et al., 2007). Therefore, V263G is considered to be a disease-causing mutation. The variant is found in NOONAN panel(s).
Integrated Genetics/Laboratory Corporation of America RCV000523845 SCV000920144 likely pathogenic Rasopathy 2018-07-30 criteria provided, single submitter clinical testing Variant summary: RAF1 c.788T>G (p.Val263Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was absent in 246246 control chromosomes tested (gnomAD). p.Val263Gly has been reported in the literature as a de novo variant in one fetal sample affected with features associated with Noonan Syndrome and Related Conditions as well as in three patients with clinical features of NSRD (LMM data). In addition, overlapping variants of the same codon have been reported to be associated with Noonan Syndrome and Related conditions (p.Val263Ala, p.V263D), suggesting this valine is critical for protein function. To our knowledge, no experimental evidence demonstrating an impact of p.Val263Gly on protein function has been reported, however p.Val263Ala resulted in robust ERK activation indicating increased and prolonged signaling through the RAS-MEK-ERK cascade (Razzaque_2007). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, with several submissions prior to 2014, and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037708 SCV000061370 likely pathogenic Noonan syndrome 2013-11-19 criteria provided, single submitter clinical testing The Val263Gly variant has now been identified by our laboratory in three individ uals with clinical features of Noonan syndrome. In addition, a different amino a cid change at the same position (Val263Ala) has also been associated with the cl inical features of Noonan syndrome (Razzaque 2007). This variant has not been i dentified in large population studies. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that thi s variant may impact the protein. Of note, individuals with pathogenic variants in exon 7 or 17 in RAF1 have a high incidence of hypertrophic cardiomyopathy (80 -95%, Razzaque 2007). In summary, the Val263Gly variant is likely to be pathogen ic, although additional information is needed to fully establish its clinical si gnificance.

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