Total submissions: 6
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Eurofins Ntd Llc |
RCV000390743 | SCV000342019 | uncertain significance | not provided | 2017-10-31 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001349385 | SCV001543728 | pathogenic | RASopathy | 2024-08-20 | criteria provided, single submitter | clinical testing | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 59 of the PTPN11 protein (p.Thr59Ala). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with Noonan syndrome (PMID: 19020799, 31324109). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 288033). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt PTPN11 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. |
| Prevention |
RCV004529475 | SCV004110052 | uncertain significance | PTPN11-related disorder | 2023-02-23 | criteria provided, single submitter | clinical testing | The PTPN11 c.175A>G variant is predicted to result in the amino acid substitution p.Thr59Ala. This variant has been reported in individuals with Noonan syndrome (Ko et al. 2008. PubMed ID: 19020799; Matyášová et al. 2019. PubMed ID: 31324109). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-112888159-A-G). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Ambry Genetics | RCV004021238 | SCV004934878 | uncertain significance | Cardiovascular phenotype | 2024-01-10 | criteria provided, single submitter | clinical testing | The c.175A>G (p.T59A) alteration is located in exon 3 (coding exon 3) of the PTPN11 gene. This alteration results from a A to G substitution at nucleotide position 175, causing the threonine (T) at amino acid position 59 to be replaced by an alanine (A). Based on data from gnomAD, the G allele has an overall frequency of <0.001% (1/250992) total alleles studied. The highest observed frequency was 0.006% (1/16256) of African alleles. This variant has been determined to be the result of a de novo mutation in one individual with features consistent with PTPN11-related RASopathy (Ko, 2008). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
| Gene |
RCV000390743 | SCV005439226 | likely pathogenic | not provided | 2024-05-29 | criteria provided, single submitter | clinical testing | Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 31324109, 34315577, 37595579, 19020799, 11992261, 9491886, 16053901, 29493581) |
| Fulgent Genetics, |
RCV005003613 | SCV005632272 | likely pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2024-04-25 | criteria provided, single submitter | clinical testing |