ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.782T>A (p.Leu261His)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000697357 SCV000825960 pathogenic Rasopathy 2018-03-05 criteria provided, single submitter clinical testing This sequence change replaces leucine with histidine at codon 261 of the PTPN11 protein (p.Leu261His). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and histidine. This variant is present in population databases (rs765642157, ExAC 0.002%). This variant has been reported to segregate with Noonan syndrome(NS) in a family (PMID: 28074573) and it has also been reported in several individual with NS (PMID: 22253195, 23756559). Experimental studies have shown that this missense change (p.Leu261His) results in enhanced ERK phosphorylation in cell transfection studies(PMID: 28074573). A different missense substitution at this codon (p.Leu261Phe) has been determined to be pathogenic (PMID: 28074573). This suggests that the leucine 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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