Total submissions: 5
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000680807 | SCV000808252 | uncertain significance | not provided | 2024-12-24 | criteria provided, single submitter | clinical testing | Has been observed in an adult patient with apparently isolated atrioventricular septal defect (PMID: 15940693); While a functional study suggested that L43F may result in a protein with increased binding affinity, further evidence is needed to verify this finding (PMID: 39012820); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22781091, 29724030, 39091798, 29493581, 39012820, 15940693) |
Labcorp Genetics |
RCV000805888 | SCV000945863 | uncertain significance | RASopathy | 2022-02-01 | criteria provided, single submitter | clinical testing | 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PTPN11 protein function. ClinVar contains an entry for this variant (Variation ID: 561500). This missense change has been observed in individual(s) with complete atrioventricular septal defect and/or Noonan syndrome (PMID: 15940693; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 43 of the PTPN11 protein (p.Leu43Phe). |
Women's Health and 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. |
Fulgent Genetics, |
RCV002493124 | SCV002777304 | uncertain significance | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2021-08-26 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV004985065 | SCV005478349 | uncertain significance | Cardiovascular phenotype | 2024-09-05 | criteria provided, single submitter | clinical testing | The p.L43F variant (also known as c.127C>T), located in coding exon 2 of the PTPN11 gene, results from a C to T substitution at nucleotide position 127. The leucine at codon 43 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been reported in congenital heart defect cohorts (Weismann et al. Am J Med Genet A. 2005 Jul 15;136(2):146-51; Sarkozy et al. Am J Med Genet A. 2006 Sep 15;140(18):1970-2). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. |