ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.782T>A (p.Leu261His) (rs765642157)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000697357 SCV001335319 likely pathogenic Rasopathy 2020-03-16 reviewed by expert panel curation The c.782T>A (p.Leu261His) variant in PTPN11 is present in 1/6064 “other” alleles in gnomAD v2.1.1; however, it is absent from gnomAD v3 (PM2 not met). It has been identified in 7 independent occurrences in patients with clinical features of a RASopathy (PS4; PMIDs: 28074573, 22253195, 23756559). A functional assay performed on this variant does not meet approved RASopathy VCEP guidelines for criteria application (PS3 not met; PMID: 28074573). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot of PTPN11 (PM1; PMID 29493581). PTPN11 has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathy based on the RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PM1, PP2.
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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