ClinVar Miner

Submissions for variant NM_000267.3(NF1):c.3827G>C (p.Arg1276Pro) (rs137854556)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Human Genetics, Inc RCV000000381 SCV000782002 pathogenic Neurofibromatosis, type 1 2016-11-01 criteria provided, single submitter clinical testing
Invitae RCV000000381 SCV000753612 pathogenic Neurofibromatosis, type 1 2018-06-08 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 1276 of the NF1 protein (p.Arg1276Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with neurofibromatosis type 1 in a single family (PMID: 9668168). ClinVar contains an entry for this variant (Variation ID: 353). Experimental studies have shown that this missense change retained its binding ability to other components, but significantly disabled GAP activity and GAP-stimulated GTP hydrolysis, suggesting that the Arg1276Pro functioned as a dominant negative form against the endogenous full-length neurofibromin (PMID: 9668168, 16513807, 26635368). This sequence change falls within a mutational hotspot region, and a different missense substitution at this codon (p.Arg1276Gln) has been determined to be pathogenic (PMID: 10712197, 15060124, 16479075, 19221814, 23668869, 27322474, 22807134). Arg1276 is known to be a critical catalytic residue in the GAP related domain of NF1, which has been found to interact with Ras and GTP, and is thought to prevent uncontrolled cell proliferation by modulating Ras activity (PMID: 9302992). This suggests that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000000381 SCV000020525 pathogenic Neurofibromatosis, type 1 1998-08-01 no assertion criteria provided literature only

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