ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.785T>G (p.Leu262Arg) (rs397507526)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000526885 SCV000659049 pathogenic Rasopathy 2017-06-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with arginine at codon 262 of the PTPN11 protein (p.Leu262Arg). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Noonan sydrome (PMID: 22253195, 28074573, 24896146). In at least 2 of these individuals, this variant has been reported to be de novo (PMID: 28074573). ClinVar contains an entry for this variant (Variation ID: 40521). Experimental studies have shown that this missense change enhances the ERK phosphorylation activity of the PTPN11 protein (PMID: 28074573). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000526885 SCV000920101 pathogenic Rasopathy 2018-10-15 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.785T>G (p.Leu262Arg) results in a non-conservative amino acid change located in the Tyrosine specific protein phosphatases domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 242174 control chromosomes (gnomAD). c.785T>G has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions including de novo occurrences and inherited occurrences showing segregation with disease (Pannone_2017, Justino_2015). These data indicate that the variant is likely to be associated with disease. A functional study, Pannone_2017, found the variant to cause a gain of function supporting the common mechanism of disease. In addition, the variant is located in a mutational hot spot, where other variants, at this position, L262F, and nearby R265Q, L261F, L261H, have been reported in affected individuals. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) RCV000106324 SCV000143817 not provided Noonan syndrome 1 no assertion provided not provided

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