Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Laboratory for Molecular Medicine, |
RCV000037608 | SCV000061269 | uncertain significance | not specified | 2017-01-18 | criteria provided, single submitter | clinical testing | The p.Gly409Ala variant in PTPN11 has been identified in at least 2 heterozygous individuals with mild features of Noonan syndrome (Zenker 2006, Lepri 2014, LMM data) and 1 compound heterozygous individual (also carried the pathogenic p.Ser 2Gly variant in SHOC2) with a clinical diagnosis of Noonan syndrome (Ekvall 2011 ). This variant segregated with mild features of Noonan syndrome in 6 relatives from 2 families (Zenker 2006, Ekvall 2011). Please note that none of the individ uals carrying the p.Gly409Ala variant had heart defects or CNS involvement. The p.Gly409Ala variant has also been identified in 12/66642 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org/; dbSNP rs201247699). Computational prediction tools and conservation analysis do not pr ovide strong support for or against an impact to the protein. These data suggest that this variant may cause mild features of Noonan syndrome, but more data is needed to determine this. In summary, the clinical significance of the p.Gly409A la variant is uncertain. |
Gene |
RCV000037608 | SCV000490756 | uncertain significance | not specified | 2016-02-20 | criteria provided, single submitter | clinical testing | The G409A variant in the PTPN11 gene has been reported to co-segregate with Noonan syndrome in five individuals from one family, however these individuals had mild features and did not have any cardiac findings (Zenker et al., 2007). Additionally, Lepri et al. (2014) reported G409A in one individual with suspected Noonan syndrome, but clinical and segregation information was not provided. G409A was also reported in a proband with severe Noonan syndrome who also harbored a de novo SHOC2 variant. A parent and sibling harbored only G409A and had mild features of Noonan syndrome(Ekvall et al., 2011). The G409A variant was not observed with any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G409A variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret G409A as a variant of uncertain significance |
Centre for Mendelian Genomics, |
RCV000626827 | SCV000747530 | uncertain significance | Neurofibroma | 2017-01-01 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000037608 | SCV000918106 | uncertain significance | not specified | 2018-04-02 | criteria provided, single submitter | clinical testing | Variant summary: PTPN11 c.1226G>C (p.Gly409Ala) results in a non-conservative amino acid change located in the PTP type protein phosphatase (IPR000242) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTPN11 causing Noonan Syndrome and Related Conditions phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The c.1226G>C has been reported in the literature in heterozygosity in individuals affected with mild features of Noonan Syndrome and Related Conditions (NSRD) in two families (Zenker 2007, Ekvall 2011) and was found in a cohort of individuals with suspected Noonan Syndrome (Lepri 2014). These reports do not provide unequivocal conclusions about association of the variant with NSRD. Co-occurrences with other pathogenic variant(s) have been reported (SHOC2 c.4A>G , p.Ser2Gly), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Labcorp Genetics |
RCV001296596 | SCV001485565 | uncertain significance | RASopathy | 2023-12-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 409 of the PTPN11 protein (p.Gly409Ala). This variant is present in population databases (rs201247699, gnomAD 0.01%). This missense change has been observed in individual(s) with suspected diagnosis of Noonan syndrome and/or features consistent with mild RASopathy (PMID: 17052965, 21548061, 24451042). ClinVar contains an entry for this variant (Variation ID: 44596). 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 with a positive predictive value of 95%. 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. |
Genome Diagnostics Laboratory, |
RCV001813326 | SCV002060831 | uncertain significance | Noonan syndrome and Noonan-related syndrome | 2020-02-01 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV002362629 | SCV002663393 | uncertain significance | Cardiovascular phenotype | 2024-12-04 | criteria provided, single submitter | clinical testing | The p.G409A variant (also known as c.1226G>C), located in coding exon 11 of the PTPN11 gene, results from a G to C substitution at nucleotide position 1226. The glycine at codon 409 is replaced by alanine, an amino acid with similar properties. This variant was reported to segregate with mild feature of Noonan syndrome (NS) in a family without cardiovascular findings (Zenker M et al. Eur J Med Genet Sep;50:43-7). This variant co-occurred with a de novo variant in the SHOC2 gene in a proband with severe/complex NS, while the PTPN11 variant was seen alone in two relatives reported to have mild features (Ekvall S et al. Am J Med Genet A, 2011 Jun;155A:1217-24). This variant has also been detected in an individual with suspected NS; however, details were limited (Lepri FR et al. BMC Med Genet, 2014 Jan;15:14). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
Fulgent Genetics, |
RCV002477095 | SCV002796298 | uncertain significance | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2024-03-02 | criteria provided, single submitter | clinical testing | |
Clinical Genetics Laboratory, |
RCV004696650 | SCV005197305 | uncertain significance | not provided | 2023-10-31 | criteria provided, single submitter | clinical testing |