ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.1506_1507delinsCC (p.Gly503Arg) (rs1566186833)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000692146 SCV000819955 pathogenic Rasopathy 2018-06-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 503 of the PTPN11 protein (p.Gly503Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with PTPN11-related disease. However, other nucleotide changes (c.1507G>A, c.1507G>C) with the same protein effect (p.Gly503Arg) have been reported in many unrelated individuals with Noonan syndrome or Leopard syndrome (PMID: 12960218, 24754368, 19077116, 18758896, 16358218, 19737548, 12717436). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, Align-GVGD) suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Gly503Glu) has been determined to be pathogenic (PMID: 18678287, 26785492). This suggests that the glycine residue is critical for PTPN11 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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