ClinVar Miner

Submissions for variant NM_002834.4(PTPN11):c.127C>T (p.Leu43Phe) (rs1566164987)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000680807 SCV000808252 likely pathogenic not provided 2018-08-21 criteria provided, single submitter clinical testing The L43F variant has been published as a pathogenic variant in association with antrioventricular septal defect (Weismann et al., 2005). The L43F variant is not observed in large population cohorts (Lek et al., 2016). The L43F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. This variant is located within the directly interacting residues between the highly conserved PTP and N-SH2 domains. In summary, this variant is likely pathogenic
Invitae RCV000805888 SCV000945863 uncertain significance Rasopathy 2019-01-10 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 43 of the PTPN11 protein (p.Leu43Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with complete atrioventricular septal defect (PMID: 15940693) and an individual affected with Noonan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 561500). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This missense change is located in a region of the PTPN11 protein where a significant number of previously reported PTPN11 missense mutations are found (PMID: 23584145, 26817465, 16358218, 16263833). These observations suggest that a missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Integrated Genetics/Laboratory Corporation of America RCV001193111 SCV001361727 uncertain significance not specified 2019-10-08 criteria provided, single submitter clinical testing Variant summary: PTPN11 c.127C>T (p.Leu43Phe) results in a non-conservative amino acid change located in the SH2 domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.127C>T has been reported in the literature in an individual affected with atrioventricular septal defect (Weismann_2005). This report does not provide unequivocal conclusions about association of the variant with Noonan Syndrome and Related Conditions. The variant is located close to a known Noonan syndrome mutation (PTPN11 p.T42A) and it is part of a group of variants located in the phosphopeptide-binding clefts in the N-terminal SH2 domain which are implicated in the intermolecular interactions of the protein with its signaling partners and which control SHP-2 translocation and activation. Mutations affecting these pockets are predicted to perturb phosphopeptide-binding specificity and/or affinity (Lappalainen_2008, Tartaglia_2006). However, to our knowledge, no experimental evidence demonstrating an impact of the variant on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1) and as likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance until additional data of clinical and functional significance become available.

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