Total submissions: 10
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Institute for Genomic Medicine |
RCV000037630 | SCV007449265 | pathogenic | Noonan syndrome 1 | 2024-02-13 | criteria provided, single submitter | clinical testing | A different nucleotide change resulting in the same amino acid substitution has been reported as pathogenic (ACMG/AMP: PS1). This variant has been reported at an elevated frequency in affected individuals/in multiple affected individuals in the literature (ACMG/AMP: PS4; PMIDs:12634870, 18470943, 25914815, 29907801, 32164556). This variant is located in a mutational hot spot and/or critical and well-established functional domain (ACMG/AMP: PM1). This variant is absent from or present at an exceedingly low frequency in gnomAD, a large-scale control population database (ACMG/AMP: PM2). This variant has been reported to occur de novo in an affected individual in the literature without parental identity confirmed (ACMG/AMP: PM6_Strong; PMIDs:23321623, 25914815). This variant occurs in a gene with a low rate of benign missense variation, in which missense alterations are a common mechanism of disease (ACMG/AMP: PP2). |
| Laboratoire Génétique Moléculaire, |
RCV000037630 | SCV006586834 | pathogenic | Noonan syndrome 1 | 2022-12-16 | criteria provided, single submitter | clinical testing | PS1;PS2;PM1;PM2;PP3;PP4;PP5 |
| Labcorp Genetics |
RCV000588173 | SCV001392879 | pathogenic | RASopathy | 2024-01-04 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 58 of the PTPN11 protein (p.Asn58Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Noonan syndrome (PMID: 12634870, 20954246, 22190897, 23321623). ClinVar contains an entry for this variant (Variation ID: 40489). 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%. This variant disrupts the p.Asn58 amino acid residue in PTPN11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15001945, 16263833, 19125092). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Ce |
RCV000033457 | SCV001246726 | pathogenic | not provided | 2017-09-01 | criteria provided, single submitter | clinical testing | |
| Genomic Research Center, |
RCV000211846 | SCV000746841 | pathogenic | Noonan syndrome | 2017-12-18 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000588173 | SCV000698063 | pathogenic | RASopathy | 2017-04-03 | criteria provided, single submitter | clinical testing | Variant summary: The PTPN11 c.174C>G (p.Asn58Lys) variant located in the mutational hotspot, SH2 domain, involves the alteration of a non-conserved nucleotide and by 4/4 in-silico tools (SNPs&GO not captured due to low reliability index) predict a damaging outcome, although these predictions have yet to be functionally assessed. This variant is absent in 122184 control chromosomes including broad and large populations from ExAC. Publications have cited this variant as a pathogenic variant and has been detected in several patients with Noonans syndrome, including multiple instances of a de novo origin (Musante_2003, Tartaglia_2006, Derbent_2010, Digilio_2011, Ezquieta_2012, Croonen_2012, Coromilas_2015, and Cizmarova_2015). Other missense variants at this residue (N58Y, N58D, N58H, and N58S) are reported in association with Noonan syndrome and are classified as pathogenic/likely pathogenic by submitters in ClinVar, strongly suggesting that the codon itself is a mutational hotspot. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as Pathogenic. |
| Fulgent Genetics, |
RCV000515267 | SCV000611302 | pathogenic | Noonan syndrome 1; Juvenile myelomonocytic leukemia; Metachondromatosis; LEOPARD syndrome 1 | 2017-05-18 | criteria provided, single submitter | clinical testing | |
| UCLA Clinical Genomics Center, |
RCV000037630 | SCV000255445 | likely pathogenic | Noonan syndrome 1 | 2012-12-04 | criteria provided, single submitter | clinical testing | |
| Laboratory for Molecular Medicine, |
RCV000211846 | SCV000061292 | pathogenic | Noonan syndrome | 2022-11-22 | criteria provided, single submitter | clinical testing | The c.174C>G, p.Asn58Lys variant in PTPN11 has been reported in at least 6 individuals with clinical features of Noonan syndrome and segregated with disease in at least 4 affected relatives from one family (Musant 2003 PMID:12634870, Tartaglia 2006 PMID:16358218, Derbent 2010 PMID:20954246, Digilio 2011 PMID:22190897, Croonen 2013 PMID:23321623, LMM data). It has also been reported by other clinical laboratories in ClinVar (Variation ID 40489) and absent from large population studies. Computational tools and conservation analyses are consistent with pathogenicity. Another variant resulting in the same missense change (c.172A>C, p.Asn58His) and two additional variants involving this codon (p.Asn58Asp and p.Asn58His) have also been reported in ClinVar as a Pathogenic variant by several clinical laboratories, including this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Noonan syndrome. ACMG/AMP criteria applied: PS4, PP1, PM2_Supporting, PM5_strong, PP3. |
| Gene |
RCV000033457 | SCV000057362 | pathogenic | not provided | 2024-09-23 | criteria provided, single submitter | clinical testing | Multiple pathogenic missense variants at this residue (p.N58D, p.N58Y, p.N58H) have been reported in association with Noonan spectrum disorders; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Missense variants in this gene are often considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 22190897, 26607044, 32164556, 12634870, 23321623, 25914815, 24803665, 28425981, 16358218, 15928039, 20954246, 15723289, 18286234, 30417923, 30050098, 29907801, 35979676, 11992261, 9491886, 16053901, 29493581) |