ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.226A>G (p.Met76Val) (rs730880999)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766677 SCV000209011 uncertain significance not provided 2014-03-24 criteria provided, single submitter clinical testing p.Met76Val (ATG>GTG): c.226 A>G in exon 3 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). The M76V variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The M76V variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Although the M76V variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties, this substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. No missense mutations in nearby residues have been reported in association with Noonan spectrum disorder or cardiomyopathy, 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).
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000761086 SCV000891001 uncertain significance Noonan syndrome 2020-09-22 criteria provided, single submitter clinical testing
Mendelics RCV000987119 SCV001136324 uncertain significance LEOPARD syndrome 2 2019-05-28 criteria provided, single submitter clinical testing
Stanford Center for Inherited Cardiovascular Disease,Stanford University RCV000159069 SCV000280431 uncertain significance not specified 2014-03-27 no assertion criteria provided clinical testing Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease

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