ClinVar Miner

Submissions for variant NM_004333.6(BRAF):c.437G>A (p.Arg146Gln) (rs557241012)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Fulgent Genetics,Fulgent Genetics RCV000764692 SCV000895824 uncertain significance Cardiofaciocutaneous syndrome 1; Lung cancer; Noonan syndrome 1; LEOPARD syndrome 3; Noonan syndrome 7 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000413361 SCV000490905 uncertain significance not specified 2015-07-02 criteria provided, single submitter clinical testing The R146Q variant has not been published as a patogenic variant nor has it been reported as a benign polymorphism to our knowledge. The 1000 Genomes Project reports R146Q was observed in 1/976 alleles (0.1%) from individuals of South Asian background, indicating it may be a rare benign variant in this population. The R146Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where amino acids with similar properties to Arginine are tolerated in mammalian 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 variants in nearby residues have been reported in the Human Gene Mutation Database in association with disease (Stenson et al., 2014), indicating 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 variant or a rare benign variant.
Invitae RCV000654945 SCV000776853 uncertain significance Rasopathy 2017-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 146 of the BRAF protein (p.Arg146Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs557241012, ExAC 0.009%). This variant has not been reported in the literature in individuals with BRAF-related disease. ClinVar contains an entry for this variant (Variation ID: 372564). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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